Substituted benzopyran derivatives for the treatment of inflammation

ABSTRACT

A class of benzopyran, derivatives is described for use in treating cyclooxygenase-2 mediated disorders. Compounds of particular interest are defined by Formula I′ 
                         
wherein X, A 1 , A 2 , A 3 , A 4 , R, R″, R 1  and R 2  are as described in the specification.

This is a continuation of prior application Ser. No. 09/496,695 filed onFeb. 2, 2000, now U.S. Pat. No. 6,806,288, and is a continuation ofapplication Ser. No. 09/062,537, filed Apr. 17, 1998, now U.S. Pat. No.6,034,256, which claims priority from U.S. Provisional Application Ser.No. 60/044,485, filed Apr. 21, 1997.

FIELD OF THE INVENTION

This invention is in the field of anti-inflammatory pharmaceuticalagents and specifically relates to compounds, compositions and methodsfor treating cyclooxygenase-2 mediated disorders, such as inflammationand inflammation-related disorders.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process and theinhibition of prostaglandin production, especially production of PGG₂,PGH₂ and PGE₂, has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).The recent discovery of an inducible enzyme associated with inflammation(named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”)provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects.

The references below that disclose antiinflammatory activity, showcontinuing efforts to find a safe and effective antiinflammatory agent.The novel benzopyran, dihydroquinoline, benzothiopyran anddihydronapthalene derivatives disclosed herein are such safe and alsoeffective antiinflammatory agents furthering such efforts. Thesubstituted benzopyran, dihydroquinoline, benzothiopyran anddihydronapthalene derivatives disclosed herein preferably selectivelyinhibit cyclooxygenase-2 over cyclooxygenase-1.

U.S. Pat. No. 5,618,843, to Fisher et al., generically describes acidsubstituted bicyclic moieties as IIb/IIIA antagonists. WO 94/13659,published Jun. 23, 1994, describes fused benzo compounds for thetreatment of CNS disorders. Manrao et al. (J. Indian. Counc. Chem., 12,38–41 (1996)) describes carboxy coumarinimide derivatives and theirantifungal activity. U.S. Pat. No. 5,348,976, to Shibata et al.,describes amide substituted benzopyrans as antifungals.

WO96/40110, published Dec. 19, 1996, describes benzopyran derivatives astyrosine kinase modulators. Loiodice et al. (Tetrahedron, 6, 1001–11(1995)) describe the preparation of 6-chloro-2,3-dihydro-4H-1-benzopyrancarboxylic acids.

Clemence et al. (J. Med. Chem., 31, 1453–62, (1988)) describe4-hydroxy-3-quinolinecarbooxylic acids as starting material in thepreparation of antiinflammatories. Lazer, et al. (J. Med. Chem., 40,980–89 (1997)) describe benzothiopyran carboxylates as starting materialin the preparation of antiinflammatories.

Benzopyran-3-carboxylic acids have been described. Gupta et al. (IndianJ. Chem., 21B, 344–347 (1982)) describe chromene-3-carboxylic acid as anintermediate in the preparation of centrally acting muscle relaxants.Rene and Royer (Eur. J. Med. Chem.—Chim. Ther., 10, 72–78 (1975))describe the preparation of chromene-3-carboxylic acid. U.S. Pat. No.4,665,202, to Rimbault et al., describes 2-phenyl substituted flavenesand thioflavenes as 5-lipoxygenase inhibitors. U.S. Pat. No. 5,250,547,to Lochead et al., describe benzopyran derivatives as 5-lipoxygenaseinhibitors. Satoh et al. [J. Med. Chem., 36, 3580–94 (1993)] describesubstituted chromenes as 5-lipoxygenase inhibitors. U.S. Pat. No.5,155,130, to Stanton et al. describes substituted chromenes as5-lipoxygenase inhibitors, and specifically6-benzyloxy-2H-benzopyran-3-carboxylic acid as an intermediate.

However, compounds of the current invention have not been described ascyclooxygenase inhibitors.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating cyclooxygenase-2 medicateddisorders is defined by Formula I′:

wherein X is selected from O, S, CR^(c)R^(b) and NR^(a);

wherein R^(a) is selected from hydrido, C₁–C₃-alkyl, (optionallysubstituted phenyl)-C₁–C₃-alkyl, alkylsulfonyl, phenylsulfonyl,benzylsulfonyl, acyl and carboxy-C₁–C₆-alkyl;

wherein each of R^(b) and R^(c) is independently selected from hydrido,C₁–C₃-alkyl, phenyl-C₁–C₃-alkyl, C₁–C₃-perfluoroalkyl, chloro,C₁–C₆-alkylthio, C₁–C₆-alkoxy, nitro, cyano and cyano-C₁–C₃-alkyl;

oe wherein CR^(c)R^(b) form a cyclopropyl ring;

wherein R is selected from carboxyl, aminocarbonyl,C₁–C₆-alkylsulfonylaminocarbonyl and C₁–C₆-alkoxycarbonyl;

wherein R″ is selected from hydrido, phenyl, thienyl, C₂–C₆-alkynyl andC₂–C₆-alkenyl;

wherein R¹ is selected from C₁–C₃-perfluoroalkyl, chloro,C₁–C₆-alkylthio, C₁–C₆-alkoxy, nitro, cyano and cyano-C₁–C₃-alkyl;

wherein R² is one or more radicals independently selected from hydrido,halo, C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl, halo-C₂–C₆-alkynyl,aryl-C₁–C₃-alkyl, aryl-C₂–C₆-alkynyl, aryl-C₂–C₆-alkenyl, C₁–C₆-alkoxy,methylenedioxy, C₁–C₆-alkylthio, C₁–C₆-alkylsulfinyl, —O(CF₂)₂O—,aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁–C₆-alkoxy-C₁–C₆-alkyl, aryl-C₁–C₆-alkyloxy,heteroaryl-C₁–C₆-alkyloxy, aryl-C₁–C₆-alkoxy-C₁–C₆-alkyl,C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy, C₁–C₆-haloalkylthio,C₁–C₆-haloalkylsulfinyl, C₁–C₆-haloalkylsulfonyl,C₁–C₃-(haloalkyl-C₁–C₃-hydroxyalkyl, C₁–C₆-hydroxyalkyl,hydroxyimino-C₁–C₆-alkyl, C₁–C₆-alkylamino, arylamino,aryl-C₁–C₆-alkylamino, heteroarylamino, heteroaryl-C₁–C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁–C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁–C₆-alkylaminosulfonyl, heteroaryl-C₁–C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, aryl-C₁–C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁–C₆-alkylcarbonyl, heteroaryl-C₁–C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁–C₆-alkoxycarbonyl,formyl, C₁–C₆-haloalkylcarbonyl and C₁–C₆-alkylcarbonyl; and

wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least two of A¹, A²;A³ and A⁴ are carbon;

or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, guinoxalinyl anddibenzofuryl;

or an isomer or pharmaceutically acceptable salt thereof.

A related class of compounds useful in treating cyclooxygenase-2medicated disorders is defined by Formula I:

wherein X is selected from O or S or NR^(a);

wherein R^(a) is alkyl;

wherein R is selected from carboxyl, aminocarbonyl,alkylsulfonylaminocarbonyl and alkoxycarbonyl;

wherein R¹ is selected from haloalkyl, alkyl, aralkyl, cycloalkyl andaryl optionally substituted with one or more radicals selected fromalkylthio, nitro and alkylsulfonyl; and

wherein R² is one or more radicals selected from hydrido, halo, alkyl,aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy,haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino,heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl,alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl,alkylsulfonyl, optionally substituted aryl, optionally substitutedheteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl,aminocarbonyl, and alkylcarbonyl;

or wherein R² together with ring A forms a naphthyl radical;

or an isomer or pharmaceutically acceptable salt thereof.

Compounds of the present invention would be useful for, but not limitedto, the treatment of inflammation in a subject, and for treatment ofother cyclooxygenase-2 mediated disorders, such as, as an analgesic inthe treatment of pain and headaches, or as an antipyretic for thetreatment of fever. For example, compounds of the invention would beuseful to treat arthritis, including but not limited to rheumatoidarthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,systemic lupus erythematosus and juvenile arthritis. Such compounds ofthe invention would be useful in the treatment of asthma, bronchitis,menstrual cramps, preterm labor, tendinitis, bursitis, liver diseaseincluding hepatitis, skin-related conditions such as psoriasis, eczema,burns and dermatitis, and from post-operative inflammation includingfrom ophthalmic surgery such as cataract surgery and refractive surgery.Compounds of the invention also would be useful to treatgastrointestinal conditions such as inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome and ulcerative colitis.Compounds of the invention would be useful in treating inflammation insuch diseases as migraine headaches, periarteritis nodosa, thyroiditis,aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type Idiabetes, neuromuscular junction disease including myasthenia gravis,white matter disease including multiple sclerosis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,nephritis, hypersensitivity, swelling occurring after injury includingbrain edema, myocardial ischemia, and the like. The compounds would alsobe useful in the treatment of ophthalmic diseases, such as retinitis,conjunctivitis, retinopathies, uveitis, ocular photophobia, and of acuteinjury to the eye tissue. The compounds would also be useful in thetreatment of pulmonary inflammation, such as that associated with viralinfections and cystic fibrosis. The compounds would also be useful forthe treatment of certain central nervous system disorders, such ascortical dementias including Alzheimer's disease, and central nervoussystem damage resulting from stroke, ischemia and trauma. The compoundsof the invention are useful as anti-inflammatory agents, such as for thetreatment of arthritis, with the additional benefit of havingsignificantly less harmful side effects. These compounds would also beuseful in the treatment of allergic rhinitis, respiratory distresssyndrome, endotoxin shock-syndrome, and liver disease. The compoundswould also be useful in the treatment of pain, but not limited topostoperative pain, dental pain, muscular pain, and pain resulting fromcancer. The compounds would be useful for the treatment of dementias.The term “treatment” includes partial or total inhibition of thedementia, including Alzheimer's disease, vascular dementia,multi-infarct dementia, pre-senile dementia, alcoholic dementia, andsenile dementia.

The method above would be useful for, but not limited to, treating andpreventing inflammation-related cardiovascular disorders in a subject.The method would be useful for treatment and prevention of vasculardiseases, coronary artery disease, aneurysm, arteriosclerosis,atherosclerosis including cardiac transplant atherosclerosis, myocardialinfarction, embolism, stroke, thrombosis, including venous thrombosis,angina including unstable angina, coronary plaque inflammation,bacterial-induced inflammation including Chlamydia-induced inflammation,viral induced inflammation, and inflammation associated with surgicalprocedures such as vascular grafting including coronary artery bypasssurgery, revascularization procedures including angioplasty, stentplacement, endarterectomy, or other invasive procedures involvingarteries, veins and capillaries.

The compounds would be useful for, but not limited to, the treatment ofangiogenesis-related disorders in a subject. According to the presentinvention, the compounds are administered to a subject in need ofangiogenesis inhibition. The method would be useful for treatment ofneoplasia, including metastasis; ophthalmological conditions such ascorneal graft rejection, ocular neovascularization, retinalneovascularization including neovascularization following injury orinfection, diabetic retinopathy, macular degeneration, retrolentalfibroplasia and neovascular glaucoma; ulcerative diseases such asgastric ulcer; pathological, but non-malignant, conditions such ashemangiomas, including invantile hemaginomas, angiofibroma of thenasopharynx and avascular necrosis of bone; and disorders of the femalereproductive system such as endometriosis.

Compounds of the invention would be useful for the prevention ortreatment of neoplasia including cancer, such as colorectal cancer,brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelialcarcinoma) such as basal cell carcinoma, adenocarcinoma,gastrointestinal cancer such as lip cancer, mouth cancer, esophogealcancer, small bowel cancer and stomach cancer, colon cancer, livercancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer,lung cancer, breast cancer and skin cancer, such as squamus cell andbasal cell cancers, prostate cancer, renal cell carcinoma, and otherknown cancers that effect epithelial cells throughout the body.Preferably, neoplasia is selected from gastrointestinal cancer, livercancer, bladder cancer, pancreas cancer, ovary cancer, prostate cancer,cervical cancer, lung cancer, breast cancer and skin cancer, such assquamus cell and basal cell cancers. The compounds can also be used totreat the fibrosis which occurs with radiation therapy. The method canbe used to treat subjects having adenomatous polyps, including thosewith familial adenomatous polyposis (FAP). Additionally, the method canbe used to prevent polyps from forming in patients at risk of FAP.

The administration of compounds of the present invention may be usedalone or in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of neoplasia. Alternatively,the compounds described herein may be used in conjunctive therapy. Byway of example, the compounds may be administered alone or inconjunction with other antineoplastic agents or other growth inhibitingagents or other drugs or nutrients.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which couldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents. Alternatively, other anti-neoplasticagents, such as metallomatrix proteases (MMP), SOD mimics or α_(ν)β₃inhibitors may be used.

A first family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists of antimetabolite-typeantineoplastic agents. Suitable antimetabolite antineoplastic agents maybe selected from the group consisting of 5-FU-fibrinogen, acanthifolicacid, aminothiadiazole, brequinar sodium, carmofur, Ciba-GeigyCGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate,cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine,dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine,Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabinephosphate, 5-fluorouracil, N-(2′-furanidyl)-5-fluorouracil, DaiichiSeiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618,methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCINSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567,Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi ChemicalPL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF,trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinaseinhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from the group consisting ofShionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone,Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from the group consisting of Taiho 4181-A, aclarubicin,actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative,Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins,anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859,Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-MyersBMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B,Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b,Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, NipponKayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181–2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents selected from the groupconsisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate,Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, FujisawaFR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglumide, Invitron protease nexin I, TobishiRA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine,retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976,SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharmSP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed,SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237,Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680,taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa HakkoUCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM-534.

Examples of radioprotective agents which may be used in combination withcompounds of the present invention are AD-5, adchnon, amifostineanalogues, detox, dimesna, 1–102, MM-159, N-acylated-dehydroalanines,TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofentransdermal, nabumetone, superoxide dismutase (Chiron) and superoxidedismutase Enzon.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

The present compounds may also be used in co-therapies, partially orcompletely, in place of other conventional antiinflammatories, such astogether with steroids, NSAIDS, iNOS inhibitors, 5-lipoxygenaseinhibitors, LTB₄ receptor antagonists and LTA₄ hydrolase inhibitors.

Suitable LTA₄ hydrolase inhibitors include RP-64966,(S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid benzyl ester(Scripps Res. Inst.),N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine(Searle), 7-(4-(4-ureidobenzyl)phenyl)heptanoic acid (Rhone-PoulencRorer), and 3-(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithiumsalt (Searle).

Suitable LTB₄ receptor antagonists include, among others, ebselen,linazolast, ontazolast, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-615, Merck compound MAFP, Terumocompound TMK-688, Tanabe compound T-0757, Lilly compounds LY-213024,LY-210073, LY223982, LY233469, and LY255283, LY-293111, 264086 and292728, ONO compounds ONO-LB457, ONO-4057, and ONO-LB-448, Shionogicompound S-2474, calcitrol, Lilly compounds Searle compounds SC-53228,SC-41930, SC-50605 and SC-51146, Warner Lambert compound BPC 15,SmithKline Beecham compound SB-209247 and SK&F compound SKF-104493.Preferably, the LTB₄ receptor antagonists are selected from calcitrol,ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmarkcompound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, andTerumo compound TMK-688.

Suitable 5-LO inhibitors include, among others, Abbott compoundsA-76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed CMI-392, EisaiE-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML-3000,Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen,linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton,pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadremphosphate, and bunaprolast.

The present compounds may also be used in combination therapies withopioids and other analgesics, including narcotic analgesics, Mu receptorantagonists, Kappa receptor antagonists, non-narcotic (i.e.non-addictive) analgesics, monoamine uptake inhibitors, adenosineregulating agents, cannabinoid derivatives, Substance P antagonists,neurokinin-1 receptor antagonists and sodium channel blockers, amongothers. More preferred would be combinations with compounds selectedfrom morphine, meperidine, codeine, pentazocine, buprenorphine,butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone,Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP-60180,HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirfentanil, amitriptyline, DuP631,Tramadol [(−) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99, 994, and CP-99, 994.

The compounds can be used in combination with one or moreantihistamines, decongestants, diuretics, antitussive agents or withother agents previously known to be effective in combination withantiinflammatory agents.

The term “prevention” includes either preventing the onset of clinicallyevident cardiovascular disorders altogether or preventing the onset of apreclinically evident stage of cardiovascular disorder in individuals.This includes prophylactic treatment of those at risk of developing acardiovascular disorder.

The phrase “therapeutically-effective” is intended to qualify the amountof each agent which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The present invention preferably includes compounds which selectivelyinhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably, thecompounds have a cyclooxygenase-2 IC₅₀ of less than about 0.5 μM, andalso have a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 50, and more preferably of atleast 100. Even more preferably, the compounds have a cyclooxygenase-1IC₅₀ of greater than about 5 μM. Such preferred selectivity may indicatean ability to reduce the incidence of common NSAID-induced side effects.

A preferred class of compounds consists of those compounds of Formula Iwherein X is oxygen or sulfur; wherein R is selected from carboxyl,lower alkyl, lower aralkyl and lower alkoxycarbonyl; wherein R¹ isselected from lower haloalkyl, lower cycloalkyl and phenyl; and whereinR² is one or more radicals selected from hydrido, halo, lower alkyl,lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino,nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- or 6-memberedheteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5- or6-membered nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl,optionally substituted phenyl, lower aralkylcarbonyl, and loweralkylcarbonyl; or wherein R² together with ring A forms a naphthylradical; or an isomer or pharmaceutically acceptable salt thereof.

A more preferred class of compounds consists of those compounds ofFormula I wherein X is oxygen or sulfur; wherein R is selected fromcarboxyl; wherein R¹ is selected from lower haloalkyl; and wherein R² isone or more radicals selected from hydrido, halo, lower alkyl, lowerhaloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl,lower alkylaminosulfonyl, 5- or 6-membered heteroarylalkylaminosulfonyl,lower aralkylaminosulfonyl; lower alkylsulfonyl, 6-membered nitrogencontaining heterocyclosulfonyl, optionally substituted phenyl, loweraralkylcarbonyl, and lower alkylcarbonyl; or wherein R² together withring A forms a naphthyl radical; or an isomer or pharmaceuticallyacceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I wherein R is carboxyl; wherein R¹ is selected fromfluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl,dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; andwherein R² is one or more radicals selected from hydrido, chloro,fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl,isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy,trifluoromethyl, difluoromethyl, trifluoromethoxy, amino,N,N-dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl,N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro,N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl,N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl,N,N-dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl,N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl,2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or wherein R²together with ring A forms a naphthyl radical; or an isomer orpharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I wherein R is carboxyl; wherein R¹ is trifluoromethyl orpentafluorethyl; and wherein R² is selected from one or more radicalshydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl,tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy,N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl,N-(2-furylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl,N-methylaminosulfonyl, N-(2,2-dimethylethyl)aminosulfonyl,dimethylaminosulfonyl, 2-methylpropylaminosulfonyl,N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; orwherein R² together with ring A forms a naphthyl radical; or an isomeror pharmaceutically acceptable salt thereof.

A preferred-class of compounds consists of those compounds of Formula I′wherein X is selected from O, S, CR^(c)R^(b) and NR^(a); wherein R^(a)is selected from hydrido, C₁–C₃-alkyl, (optionally substitutedphenyl)-C₁–C₃-alkyl, acyl and carboxy-C₁–C₆-alkyl; wherein each of R^(b)and R^(b) is independently selected from hydrido, C₁–C₃-alkyl,phenyl-C₁–C₃-alkyl, C₁–C₃-perfluoroalkyl, chloro, C₁–C₆-alkylthio,C₁–C₆-alkoxy, nitro, cyano and cyano-C₁–C₃-alkyl; wherein R is selectedfrom carboxyl, aminocarbonyl, C₁–C₆-alkylsulfonylaminocarbonyl andC₁–C₆-alkoxycarbonyl; wherein R′ is selected from hydrido, phenyl,thienyl and C₂–C₆-alkenyl; wherein R¹ is selected fromC₁–C₃-perfluoroalkyl, chloro, C₁–C₆-alkylthio, C₁–C₆-alkoxy, nitro,cyano and cyano-C₁–C₃-alkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁–C₆-alkyl, C₂–C₆-alkenyl,C₂–C₆-alkynyl, halo-C₂–C₆-alkynyl, aryl-C₁–C₃-alkyl, aryl-C₂–C₆-alkynyl,aryl-C₂–C₆-alkenyl, C₁–C₆-alkoxy, methylenedioxy, C₁–C₆-alkylthio,C₁–C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁–C₆-alkoxy-C₁–C₆-alkyl, aryl-C₁–C₆-alkyloxy,heteroaryl-C₁–C₆-alkyloxy, aryl-C₁–C₆-alkoxy-C₁–C₆-alkyl,C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy, C₁–C₆-haloalkylthio,C₁–C₆-haloalkylsulfinyl, C₁–C₆-haloalkylsulfonyl,C₁–C₃-(haloalkyl-C₁–C₃-hydroxyalkyl, C₁–C₆-hydroxyalkyl,hydroxyimino-C₁–C₆-alkyl, C₁–C₆-alkylamino, arylamino,aryl-C₁–C₆-alkylamino, heteroarylamino, heteroaryl-C₁–C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁–C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁–C₆-alkylaminosulfonyl, heteroaryl-C₁–C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, aryl-C₁–C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁–C₆-alkylcarbonyl, heteroaryl-C₁–C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁–C₆-alkoxycarbonyl,formyl, C₁–C₆-haloalkylcarbonyl and C₁–C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least three of A¹, A², A³ and A⁴are carbon; or wherein R² together with ring A forms a naphthyl orquinolyl radical; or an isomer or pharmaceutically acceptable saltthereof.

A more preferred class of compounds consists of those compounds ofFormula I′ wherein X is selected from O, S and NR^(a); wherein R^(a) isselected from hydrido, C₁–C₃-alkyl and (optionally substitutedphenyl)methyl; wherein R′ is selected from hydrido and C₂–C₆-alkenyl;wherein R is carboxyl; wherein R¹ is selected from C₁–C₃-perfluoroalkyl;wherein R² is one or more radicals independently selected from hydrido,halo, C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl, halo-C₂–C₆-alkynyl,phenyl-C₂–C₆-alkyl, phenyl-C₂–C₆-alkynyl, phenyl-C₂–C₆-alkenyl,C₁–C₃-alkoxy, methylenedioxy, C₁–C₃-alkoxy-C₁–C₃-alkyl, C₁–C₃-alkylthio,C₁–C₃-alkylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,C₁–C₃-haloalkyl-C₁–C₃-hydroxyalkyl, phenyl-C₁–C₃-alkyloxy-C₁–C₃-alkyl,C₁–C₃-haloalkyl, C₁–C₃-haloalkoxy, C₁–C₃-haloalkylthio,C₁–C₃-hydroxyalkyl, C₁–C₃-alkoxy-C₁–C₃-alkyl, hydroxyimino-C₁–C₃-alkyl,C₁–C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁–C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁–C₆-alkyl)aminosulfonyl, phenyl-C₁–C₃-alkylsulfonyl, 5-to 8-membered heterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, optionallysubstituted phenyl, optionally substituted 5- to 9-membered heteroaryl,phenyl-C₁–C₆-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl,4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl,4-methoxyphenylcarbonyl, aminocarbonyl, formyl, and C₁–C₆-alkylcarbonyl;wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least three of A¹, A²,A³ and A⁴ are carbon; or wherein R² together with ring A forms anaphthyl, benzofurylphenyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I′ wherein X is selected from O, S and NR^(a); wherein R^(a) isselected from hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl,(4-chloromethyl)benzyl, (4-methoxy)benzyl, and (4-cyano)benzyl,(4-nitro)benzyl; wherein R is carboxyl; wherein R′ is selected fromhydrido and ethenyl; wherein R¹ is selected from trifluoromethyl andpentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, nitro, cyano, amino, aminosulfonyl,N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl,N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl,phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenylsubstituted with one or more radicals selected from chloro, fluoro,bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl,thienyl substituted with chloro, furyl, furyl substituted with chloro,benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl,formyl and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴are independently selected from carbon and nitrogen with the provisothat at least three of A¹, A², A³ and A⁴ are carbon; or wherein R²together with ring A forms a naphthyl, or quinolyl radical; or an isomeror pharmaceutically acceptable salt thereof.

Within Formula I′ there is a subclass of chromene compounds wherein X isO; wherein R is carboxyl; wherein R″ is selected from hydrido andC₂–C₆-alkenyl; wherein R¹ is selected from C₁–C₃-perfluoroalkyl; whereinR² is one or more radicals independently selected from hydrido, halo,C₁–C₆-alkyl, phenyl-C₁–C₆-alkyl, phenyl-C₂–C₆-alkynyl,phenyl-C₂–C₆-alkenyl, C₁–C₆-alkoxy, phenyloxy, 5- or 6-memberedheteroaryloxy, phenyl-C₁–C₆-alkyloxy, 5- or 6-memberedheteroaryl-C₁–C₆-alkyloxy, C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy,N-(C₁–C₆-alkyl)amino, N,N-di-(C₁–C₆-alkyl)amino, N-phenylamino,N-(phenyl-C₁–C₆-alkyl)amino, N-heteroarylamino,N-(heteroaryl-C₁–C₆-alkylamino, nitro, amino, aminosulfonyl,N-(C₁–C₆-alkyl)aminosulfonyl, N,N-di-(C₁–C₆-alkyl)aminosulfonyl,N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁–C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁–C₆-alkyl)aminosulfonyl, 5- to 8-memberedheterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, optionally substitutedphenyl, optionally substituted 5- or 6-membered heteroaryl,phenyl-C₁–C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl,aminocarbonyl, and C₁–C₆-alkylcarbonyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or anisomer or pharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I′ wherein X is O; wherein R is carboxyl; wherein R″ is selectedfrom hydrido and ethenyl; wherein R¹ is selected from trifluoromethyland pentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; and wherein one of the A ring atoms A¹, A², A³ and A⁴ isnitrogen and the other three are carbon; or an isomer orpharmaceutically acceptable salt thereof.

Another even more preferred class of compounds consists of thosecompounds of Formula I′ wherein X is O; wherein R is carboxyl; whereinR″ is selected from hydrido and ethenyl; wherein R¹ is selected fromtrifluoromethyl and pentafluoroethyl; wherein R² is one or more radicalsindependently selected from hydrido, chloro, bromo, fluoro, iodo,methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon;or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I′ there is another subclass of benzothiopyran compoundswherein X is S; wherein R is carboxyl; wherein R¹ is selected fromC₁–C₃-perfluoroalkyl; wherein R² is one or more radicals independentlyselected from hydrido, halo, C₁–C₆-alkyl, phenyl-C₁–C₆-alkyl,phenyl-C₂–C₆-alkynyl, phenyl-C₂–C₆-alkenyl, C₁–C₆-alkoxy, phenyloxy, 5-or 6-membered heteroaryloxy, phenyl-C₁–C₆-alkyloxy, 5- or 6-memberedheteroaryl-C₁–C₆-alkyloxy, C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy,C₁–C₆-alkylamino, N-phenylamino, N-(phenyl-C₁–C₆-alkyl)amino,N-heteroarylamino, N-(heteroaryl-C₁–C₆-alkylamino, nitro, amino,aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl,N-heteroarylaminosulfonyl, N-(phenyl-C₁–C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁–C₆-alkyl)aminosulfonyl, 5- to 8-memberedheterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, optionally substitutedphenyl, optionally substituted 5- or 6-membered heteroaryl,phenyl-C₁–C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl,aminocarbonyl, and C₁–C₆-alkylcarbonyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or anisomer or pharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I′ wherein X is S; wherein R is carboxyl; wherein R″ is selectedfrom hydrido and ethenyl; wherein R¹ is selected from trifluoromethyland pentafluoroethyl; wherein R² is one or more radicals independentlyselected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl,3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon;or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I′ there is a third subclass of dihydroquinolinecompounds wherein X is NR^(a); wherein R^(a) is selected from hydrido,C₁–C₃-alkyl, phenyl-C₁–C₃-alkyl, acyl and carboxy-C₁–C₃-alkyl; wherein Ris carboxyl; wherein R¹ is selected from C₁–C₃-perfluoroalkyl; whereinR² is one or more radicals independently selected from hydrido, halo,C₁–C₆-alkyl, phenyl-C₁–C₆-alkyl, phenyl-C₂–C₆-alkynyl,phenyl-C₂–C₆-alkenyl, C₁–C₆-alkoxy, phenyloxy, 5- or 6-memberedheteroaryloxy, phenyl-C₁–C₆-alkyloxy, 5- or 6-memberedheteroaryl-C₁–C₆-alkyloxy, C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy,C₁–C₆-alkylamino, N-phenylamino, N-(phenyl-C₁–C₆-alkyl)amino,N-heteroarylamino, N-(heteroaryl-C₁–C₆-alkylamino, nitro, amino,aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl,N-heteroarylaminosulfonyl, N-(phenyl-C₁–C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁–C₆-alkyl)aminosulfonyl, 5- to 8-memberedheterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, optionally substitutedphenyl, optionally substituted 5- or 6-membered heteroaryl,phenyl-C₁–C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl,aminocarbonyl, and C₁–C₆-alkylcarbonyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or anisomer or pharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I′ wherein X is NR^(a); wherein R^(a) is selected from hydrido,methyl, ethyl, (4-trifluoromethyl)benzyl, (4-chloromethyl)benzyl,(4-methyoxy)benzyl, (4-cyano)benzyl, and (4-nitro)benzyl; wherein R iscarboxyl; wherein R″ is selected from hydrido and ethenyl; wherein R¹ isselected from trifluoromethyl and pentafluoroethyl; wherein R² is one ormore radicals independently selected from hydrido, chloro, bromo,fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl,1-pentynyl, 3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon;or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I′ there is a fourth subclass of compounds wherein X isselected from O, S and NR^(a); wherein R^(a) is selected from hydrido,C₁–C₃-alkyl, phenyl-C₁–C₃-alkyl, acyl and carboxy-C₁–C₃-alkyl; wherein Ris selected from carboxyl; wherein R¹ is selected fromC₁–C₃-perfluoroalkyl; wherein the A ring atoms A¹, A², A³ and A⁴ areindependently selected from carbon and nitrogen with the proviso that atleast three of A¹, A², A³ and A⁴ are carbon; and wherein R² togetherwith ring A forms a naphthyl or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds ofFormula I′ wherein X is selected from O, S and NR^(a); wherein R^(a) isselected from hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl,(4-chloromethyl)benzyl, (4-methoxy)benzyl, and (4-cyano)benzyl,(4-nitro)benzyl; wherein R is carboxyl; wherein R′ is selected fromhydrido and ethenyl; wherein R¹ is selected from trifluoromethyl andpentafluoroethyl; wherein the A ring atoms A¹, A², A³ and A⁴ areindependently selected from carbon and nitrogen with the proviso that atleast three of A¹, A², A³ and A⁴ are carbon; or wherein R² together withring A forms a naphthyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.

Within Formula I there is a subclass of compounds of high interestrepresented by Formula II:

wherein X is selected from O, NR^(a) and S;

wherein R² is lower haloalkyl;

wherein R³ is selected from hydrido, and halo;

wherein R⁴ is selected from hydrido, halo, lower alkyl, lowerhaloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkylaminosulfonyl, loweraralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, and 5- or6-membered nitrogen containing heterocyclosulfonyl;

wherein R⁵ is selected from hydrido, lower alkyl, halo, lower alkoxy,and aryl; and

wherein R⁶ is selected from hydrido, halo, lower alkyl, lower alkoxy,and aryl;

or an isomer or pharmaceutically acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula II wherein R² is trifluoromethyl or pentafluoroethyl; whereinR³ is selected from hydrido, chloro, and fluoro; wherein R⁴ is selectedfrom hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl,trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl,isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl,phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, andmorpholinosulfonyl; wherein R⁵ is selected from hydrido, methyl, ethyl,isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; andwherein R⁶ is selected from hydrido, chloro, bromo, fluoro, methyl,ethyl, tert-butyl, methoxy, and phenyl; or an isomer or pharmaceuticallyacceptable salt thereof.

Within Formula I there is a subclass of compounds of high interestrepresented by Formula IIa:

wherein R³ is selected from hydrido, lower alkyl, lower hydroxyalkyl,lower alkoxy and halo;

wherein R⁴ is selected from hydrido, halo, lower alkyl, lower alkylthio,lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl, loweralkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl, cyano,lower haloalkylthio, substituted or unsubstituted phenylcarbonyl, lowerhaloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkylaminosulfonyl, loweraralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6-memberedheteroaryl, lower hydrooxyalkyl, optionally substituted phenyl and 5- or6-membered nitrogen containing heterocyclosulfonyl;

wherein R⁵ is selected from hydrido, lower alkyl, halo, lower haloalkyl,lower alkoxy, and phenyl; and

wherein R⁶ is selected from hydrido, halo, cyano, hydrooxyiminomethyl,lower hydroxyalkyl, lower alkynyl, phenylalkynyl, lower alkyl, loweralkoxy, formyl and phenyl;

or an isomer or pharmaceutically acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula IIa wherein R³ is selected from hydrido, and chloro; whereinR⁴ is selected from chloro, methyl, tert-butyl, methylthio,trifluoromethyl, difluoromethyl, pentafluoromethyl,trifluoromethylsulfide, trifluoromethooxy, cyano, substituted orunsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl;wherein R⁵ is selected from hydrido, methyl, tert-butyl, chloro; andwherein R⁶ is selected from hydrido, chloro, thienyl,hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, andsubstituted or unsubstituted phenyl; or an isomer or pharmaceuticallyacceptable salt thereof.

Within Formula I there is a subclass of compounds of high interestrepresented by Formula IIb

wherein R³ is selected from hydrido, lower alkyl, lower hydroxyalkyl,lower alkoxy and halo;

wherein R⁴ is selected from hydrido, halo, lower alkyl, lower alkylthio,lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl, loweralkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl, cyano,lower haloalkylthio, substituted or unsubstituted phenylcarbonyl, lowerhaloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkylaminosulfonyl, loweraralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6-memberedheteroaryl, lower hydrooxyalkyl, optionally substituted phenyl and 5- or6-membered nitrogen containing heterocyclosulfonyl;

wherein R⁵ is selected from hydrido, lower alkyl, halo, lower haloalkyl,lower alkoxy, and phenyl; and

wherein R⁶ is selected from hydrido, halo, cyano, hydrooxyiminomethyl,lower hydroxyalkyl, lower alkynyl, phenylalkynyl, lower alkyl, loweralkoxy, formyl and phenyl;

or an isomer or pharmaceutically acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula IIb wherein R³ is selected from hydrido, and chloro; whereinR⁴ is selected from chloro, methyl, tert-butyl, methylthio,trifluoromethyl, difluoromethyl, pentafluoromethyl,trifluoromethylsulfide, trifluoromethooxy, cyano, substituted orunsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl;wherein R⁵ is selected from hydrido, methyl, tert-butyl, chloro; andwherein R⁶ is selected from hydrido, chloro, thienyl,hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, andsubstituted or unsubstituted phenyl; or an isomer or pharmaceuticallyacceptable salt thereof.

Within Formula I there is a subclass of compounds of high interestrepresented by Formula IIc:

wherein R^(a) is selected from hydrido and lower aralkyl;

wherein R³ is selected from hydrido, lower alkyl, lower hydroxyalkyl,lower alkoxy and halo;

wherein R⁴ is selected from hydrido, halo, lower alkyl, lower alkylthio,lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl, loweralkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl, cyano,lower haloalkylthio, substituted or unsubstituted phenylcarbonyl, lowerhaloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkylaminosulfonyl, loweraralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6-memberedheteroaryl, lower hydrooxyalkyl, optionally substituted phenyl and 5- or6-membered nitrogen containing heterocyclosulfonyl;

wherein R⁵ is selected from hydrido, lower alkyl, halo, lower haloalkyl,lower alkoxy, and phenyl; and

wherein R⁶ is selected from hydrido, halo, cyano, hydrooxyiminomethyl,lower hydroxyalkyl, lower alkynyl, phenylalkynyl, lower alkyl, loweralkoxy, formyl and phenyl;

or an isomer or pharmaceutically acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula IIc wherein R³ is selected from hydrido, and chloro; whereinR⁴ is selected from chloro, methyl, tert-butyl, methylthio,trifluoromethyl, difluoromethyl, pentafluoromethyl,trifluoromethylsulfide, trifluoromethooxy, cyano, substituted orunsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl;wherein R⁵ is selected from hydrido, methyl, tert-butyl, chloro; andwherein R⁶ is selected from hydrido, chloro, thienyl,hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, andsubstituted or unsubstituted phenyl; or an isomer or pharmaceuticallyacceptable salt thereof.

A family of specific compounds of particular interest within Formula Iconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

-   6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   7-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   8-ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   7,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   7-isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6,8-bis(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   7-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6,8-dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   ethyl 6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate;-   6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6,8-difluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   7-(N,N-diethylamino)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-aminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-(methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-N,N-diethylaminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6,8-dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;-   6-[[(2-furanylmethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-[(phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-[[(phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-bromo-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-hydroxymethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   5,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylic    acid;-   6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   5-methoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-(4-chlorobenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(4-hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   8-chloro-6-(4-chlorophenoxy)-2-trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylic    acid;-   6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(3-chloro-4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   8-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   8-(1H-benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   7-(1,1-dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(benzyloxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(2-furanyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-[(4-chlorophenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-[(4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-bromo-8-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(4-fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   8-chloro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6,8-diiodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-(5-chloro-2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(4-bromophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(ethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   6-chloro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acids-   6-chloro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylic    acid;-   6-chloro-4-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-(2,2,2-trifluoro-1-hydroxyethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;-   6,8-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;-   6,7-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   8-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;-   2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;-   6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   7-chloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;-   6,7-dichloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylic    acid;-   6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic    acid;-   6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;-   6,8-dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6,7-difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;-   6-bromo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;-   1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;-   6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylic    acid;-   6-chloro-1-[(4-chlorophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylic    acid;-   6-chloro-1-[(4-cyanophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-chloro-1,2-dihydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-chloro-1,2-dihydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   6-chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylic    acid;-   2-trifluoromethyl-2H-naphtho[1,2-b]pyran-3-carboxylic acid;-   2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid;-   2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid;-   5-(hydroxyethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c]pyridine-3-carboxylic    acid;-   6-(trifluoromethyl)-6h-1,3-dioxolo[4,5-g][1]benzopyran-7-carboxylic    acid; and-   3-(trifluoromethyl)-3H-benzofuro[3,2-f][1]benzopyran-2-carboxylic    acid.

A preferred family of specific compounds of particular interest withinFormulas I and I′ consists of compounds as follows:

-   (S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-7-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-8-ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-7,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-7-isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,8-bis(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-7-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-6,8-dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-ethyl 6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate;-   (S)-6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,8-difluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-7-(N,N-diethylamino)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-aminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-N,N-diethylaminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,8-dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-6-[[(2-furanylmethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-[(phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-[[(phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-bromo-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-hydroxymethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-5,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-5-methoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-(4-chlorobenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(4-hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-8-chloro-6-(4-chlorophenoxy)-2-trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(3-chloro-4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-8-(1H-benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-7-(1,1-dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(benzyloxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(2-furanyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-[(4-chlorophenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-[(4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-bromo-8-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(4-fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-8-chloro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,8-diiodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(5-chloro-2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(4-bromophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(ethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;-   (S)-6-chloro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-chloro-4-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-6,8-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-6,7-dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-8-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;-   (S)-6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-7-chloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-6,7-dichloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylic    acid;-   (S)-6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic    acid;-   (S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6,8-dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6,7-difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-bromo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylic    acid;-   (S)-6-chloro-1-[(4-chlorophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylic    acid;-   (S)-6-chloro-1-[(4-cyanophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-chloro-1,2-dihydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-chloro-1,2-dihydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylic    acid;-   (S)-6-chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylic    acid;-   (S)-2-trifluoromethyl-2H-naphtho[1,2-b]pyran-3-carboxylic acid;-   (S)-2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid;-   (S)-2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid; and-   (S)-5-(hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c]pyridine-3-carboxylic    acid.

The term “hydrido” denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form ahydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where the term “alkyl” isused, either alone or within other terms such as “haloalkyl” and“alkylsulfonyl”, it embraces linear or branched radicals having one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkyl radicals are “lower alkyl” radicals havingone to about six carbon atoms. Examples of such radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl and the like. Most preferred are lower alkylradicals having one to three carbon atoms. The term “alkenyl” embraceslinear or branched radicals having at least one carbon-carbon doublebond of two to about twenty carbon atoms or, preferably, two to abouttwelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl”radicals having two to about six carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The term “alkynyl” denotes linear or branched radicalshaving two to about twenty carbon atoms or, preferably, two to abouttwelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl”radicals having two to about ten carbon atoms. Most preferred are loweralkynyl radicals having two to about six carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like. The terms “alkenyl”and “lower alkenyl”, embrace radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. The term“halo” means halogens such as fluorine, chlorine, bromine or iodineatoms. The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1–6 carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl” meansalkyl radicals having all hydrogen atoms replaced with fluoro atoms.Examples include trifluoromethyl and pentafluoroethyl. The term“hydroxyalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms any one of which may be substituted with one ormore hydroxyl radicals. More preferred hydroxyalkyl radicals are “lowerhydroxyalkyl” radicals having one to six carbon atoms and one or morehydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The term“cyanoalkyl” embraces linear or branched alkyl radicals having one toabout ten carbon atoms any one of which may be substituted with onecyano radicals. More preferred cyanoalkyl radicals are “lowercyanoalkyl” radicals having one to six carbon atoms and one cyanoradical. Examples of such radicals include cyanomethyl. The terms“alkoxy” embrace linear or branched oxy-containing radicals each havingalkyl portions of one to about ten carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to six carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy. The “alkoxy” radicals may be further substituted with oneor more halo atoms, such as fluoro, chloro or bromo, to provide“haloalkoxy” radicals. Examples of such radicals include fluoromethoxy,chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy andfluoropropoxy. The term “aryl”, alone or in combination, means acarbocyclic aromatic system containing one or two rings wherein suchrings may be attached together in a pendent manner or may be fused. Theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,tetrahydronaphthyl, indane and biphenyl. Said “aryl” group may have 1 to3 substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro,cyano, alkoxy and lower alkylamino. The term “heterocyclyl” embracessaturated, partially saturated and unsaturated heteroatom-containingring-shaped radicals, where the heteroatoms may be selected fromnitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered heteromonocylic group containing 1 to4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothiophene, dihydropyran, dihydrofuran anddihydrothiazole. Examples of unsaturated heterocyclic radicals, alsotermed “heteroaryl” radicals, include unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl]; unsaturated condensed heterocyclic group containing1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl] and the like. The term also embraces radicals whereheterocyclic radicals are fused with aryl radicals. Examples of suchfused bicyclic radicals include benzofuran, benzothiophene, and thelike. Said “heterocyclyl” group may have 1 to 3 substituents such aslower alkyl, hydroxy, oxo, amino and lower alkylamino. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includebenzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl,dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran,benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl,furyl, and pyrazinyl. The term “sulfonyl”, whether used alone or linkedto other terms such as alkylsulfonyl, denotes respectively divalentradicals —SO₂—. “Alkylsulfonyl” embraces alkyl radicals attached to asulfonyl radical, where alkyl is defined as above. More preferredalkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one tosix carbon atoms. Examples of such lower alkylsulfonyl radicals includemethylsulfonyl, ethylsulfonyl and propylsulfonyl. “Haloalkylsulfonyl”embraces haloalkyl radicals attached to a sulfonyl radical, wherehaloalkyl is defined as above. More preferred haloalkylsulfonyl radicalsare “lower haloalkylsulfonyl” radicals having one to six carbon atoms.Examples of such lower haloalkylsulfonyl radicals includetrifluoromethylsulfonyl. The term “arylalkylsulfonyl” embraces arylradicals as defined above, attached to an alkylsulfonyl radical.Examples of such radicals include benzylsulfonyl andphenylethylsulfonyl. The terms “sulfamyl,” “aminosulfonyl” and“sulfonamidyl,” whether alone or used with terms such as“N-alkylaminosulfonyl”, “N-arylaminosulfonyl”,“N,N-dialkylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl”, denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂). The term “alkylaminosulfonyl” includes“N-alkylaminosulfonyl” and “N,N-dialkylaminosulfonyl” where sulfamylradicals are substituted, respectively, with one alkyl radical, or twoalkyl radicals. More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Examples ofsuch lower alkylaminosulfonyl radicals include N-methylaminosulfonyl,N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl. The terms“N-arylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl” denote sulfamylradicals substituted, respectively, with one aryl radical, or one alkyland one aryl radical. More preferred N-alkyl-N-arylaminosulfonylradicals are “lower N-alkyl-N-arylsulfonyl” radicals having alkylradicals of one to six carbon atoms. Examples of such lowerN-alkyl-N-aryl-aminosulfonyl radicals includeN-methyl-N-phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl.Examples of such N-aryl-aminosulfonyl radicals includeN-phenylaminosulfonyl. The term “arylalkylaminosulfonyl” embracesaralkyl radicals as described above, attached to an aminosulfonylradical. The term “heterocyclylaminosulfonyl” embraces heterocyclylradicals as described above, attached to an aminosulfonyl radical. Theterms “carboxy” or “carboxyl”, whether used alone or with other terms,such as “carboxyalkyl”, denotes —CO₂H. The term “carboxyalkyl” embracesradicals having a carboxy radical as defined above, attached to an alkylradical. The term “carbonyl”, whether used alone or with other terms,such as “alkylcarbonyl”, denotes —(C═O)—. The term “acyl” denotes aradical provided by the residue after removal of hydroxyl from anorganic acid. Examples of such acyl radicals include alkanoyl and aroylradicals. Examples of such lower alkanoyl radicals include formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, trifluoroacetyl. The term “aroyl” embraces aryl radicals witha carbonyl radical as defined above. Examples of aroyl include benzoyl,naphthoyl, and the like and the aryl in said aroyl may be additionallysubstituted. The term “alkylcarbonyl” embraces radicals having acarbonyl radical substituted with an alkyl radical. More preferredalkylcarbonyl radicals are “lower alkylcarbonyl” radicals having one tosix carbon atoms. Examples of such radicals include methylcarbonyl andethylcarbonyl. The term “haloalkylcarbonyl” embraces radicals having acarbonyl radical substituted with an haloalkyl radical. More preferredhaloalkylcarbonyl radicals are “lower haloalkylcarbonyl” radicals havingone to six carbon atoms. Examples of such radicals includetrifluoromethylcarbonyl. The term “arylcarbonyl” embraces radicalshaving a carbonyl radical substituted with an aryl radical. Morepreferred arylcarbonyl radicals include phenylcarbonyl. The term“heteroarylcarbonyl” embraces radicals having a carbonyl radicalsubstituted with a heteroaryl radical. The term “arylalkylcarbonyl”embraces radicals having a carbonyl radical substituted with anarylalkyl radical. More preferred arylcarbonyl radicals includebenzylcarbonyl. The term “heteroarylalkylcarbonyl” embraces radicalshaving a carbonyl radical substituted with a heteroarylalkyl radical.The term “alkoxycarbonyl” means a radical containing an alkoxy radical,as defined above, attached via an oxygen atom to a carbonyl radical.Preferably, “lower alkoxycarbonyl” embraces alkoxy radicals having oneto six carbon atoms. Examples of such “lower alkoxycarbonyl” esterradicals include substituted or unsubstituted methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.The term “aminocarbonyl” when used by itself or with other terms such as“aminocarbonylalkyl”, “N-alkylaminocarbonyl”, “N-arylaminocarbonyl”,“N,N-dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”,“N-alkyl-N-hydroxyaminocarbonyl” and“N-alkyl-N-hydroxyaminocarbonylalkyl”, denotes an amide group of theformula —C(═O)NH₂. The terms “N-alkylaminocarbonyl” and“N,N-dialkylaminocarbonyl” denote aminocarbonyl radicals which have beensubstituted with one alkyl radical and with two alkyl radicals,respectively. More preferred are “lower alkylaminocarbonyl” having loweralkyl radicals as described above attached to an aminocarbonyl radical.The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical. The term “N-cycloalkylaminocarbonyl”denoted aminocarbonyl radicals which have been substituted with at leastone cycloalkyl radical. More preferred are “lowercycloalkylaminocarbonyl” having lower cycloalkyl radicals of three toseven carbon atoms, attached to an aminocarbonyl radical. The term“aminoalkyl” embraces alkyl radicals substituted with amino radicals.The term “alkylaminoalkyl” embraces aminoalkyl radicals having thenitrogen atom substituted with an alkyl radical. The term“heterocyclylalkyl” embraces heterocyclic-substituted alkyl radicals.More preferred heterocyclylalkyl radicals are “5- or 6-memberedheteroarylalkyl” radicals having alkyl portions of one to six carbonatoms and a 5- or 6-membered heteroaryl radical. Examples include suchradicals as pyridylmethyl and thienylmethyl. The term “aralkyl” embracesaryl-substituted alkyl radicals. Preferable aralkyl radicals are “loweraralkyl” radicals having aryl radicals attached to alkyl radicals havingone to six carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy. The term “arylalkenyl” embraces aryl-substituted alkenylradicals. Preferable arylalkenyl radicals are “lower arylalkenyl”radicals having aryl radicals attached to alkenyl radicals having two tosix carbon atoms. Examples of such radicals include phenylethenyl. Thearyl in said arylalkenyl may be additionally substituted with halo,alkyl, alkoxy, halkoalkyl and haloalkoxy. The term “arylalkynyl”embraces aryl-substituted alkynyl radicals. Preferable arylalkynylradicals are “lower arylalkynyl” radicals having aryl radicals attachedto alkynyl radicals having two to six carbon atoms. Examples of suchradicals include phenylethynyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy. The terms benzyl and phenylmethyl are interchangeable. Theterm “alkylthio” embraces radicals containing a linear or branched alkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.An example of “alkylthio” is methylthio, (CH₃—S—). The term“haloalkylthio” embraces radicals containing a haloalkyl radical, of oneto ten carbon atoms, attached to a divalent sulfur atom. An example of“haloalkylthio” is trifluoromethylthio. The term “alkylsulfinyl”embraces radicals containing a linear or branched alkyl radical, of oneto ten carbon atoms, attached to a divalent —S(═O)— atom. The term“arylsulfinyl” embraces radicals containing an aryl radical, attached toa divalent —S(═O)— atom. The term “haloalkylsulfinyl” embraces radicalscontaining a haloalkyl radical, of one to ten carbon atoms, attached toa divalent —S(═O)— atom. The terms “N-alkylamino” and “N,N-dialkylamino”denote amino groups which have been substituted with one alkyl radicaland with two alkyl radicals, respectively. More preferred alkylaminoradicals are “lower alkylamino” radicals having one or two alkylradicals of one to six carbon atoms, attached to a nitrogen atom.Suitable “alkylamino” may be mono or dialkylamino such as N-methylamino,N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term“arylamino” denotes amino groups which have been substituted with one ortwo aryl radicals, such as N-phenylamino. The “arylamino” radicals maybe further substituted on the aryl ring portion of the radical. The term“heteroarylamino” denotes amino groups which have been substituted withone or two heteroaryl radicals, such as N-thienylamino. The“heteroarylamino” radicals may be further substituted on the heteroarylring portion of the radical. The term “aralkylamino” denotes aminogroups which have been substituted with one or two aralkyl radicals,such as N-benzylamino. The “aralkylamino” radicals may be furthersubstituted on the aryl ring portion of the radical. The terms“N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denote amino groupswhich have been substituted with one aralkyl and one alkyl radical, orone aryl and one alkyl radical, respectively, to an amino group. Theterm “arylthio” embraces aryl radicals of six to ten carbon atoms,attached to a divalent sulfur atom. An example of “arylthio” isphenylthio. The term “aralkylthio” embraces aralkyl radicals asdescribed above, attached to a divalent sulfur atom. An example of“aralkylthio” is benzylthio. The term “aralkylsulfonyl” embraces aralkylradicals as described above, attached to a divalent sulfonyl radical.The term “heterocyclylsulfonyl” embraces heterocyclyl radicals asdescribed above, attached to a divalent sulfonyl radical. The term“aryloxy” embraces aryl radicals, as defined above, attached to anoxygen atom. Examples of such radicals include phenoxy. The term“aralkoxy” embraces oxy-containing aralkyl radicals attached through anoxygen atom to other radicals. More preferred aralkoxy radicals are“lower aralkoxy” radicals having phenyl radicals attached to loweralkoxy radical as described above.

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of a compound of Formula I inassociation with at least one pharmaceutically-acceptable carrier,adjuvant or diluent.

The present invention also comprises a method of treatingcyclooxygenase-2 mediated disorders, such as inflammation, in a subject,the method comprising treating the subject having or susceptible to suchdisorder with a therapeutically-effective amount of a compound ofFormula I.

Also included in the family of compounds of Formula I are thestereoisomers thereof. Compounds of the present invention can possessone or more asymmetric carbon atoms and are thus capable of existing inthe form of optical isomers as well as in the form of racemic ornonracemic mixtures thereof. Accordingly, some of the compounds of thisinvention may be present in racemic mixtures which are also included inthis invention. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive base and then separation of the mixture of diastereoisomers bycrystallization, followed by liberation of the optically active basesfrom these salts. Examples of appropriate bases are brucine, strychnine,dehydroabietylamine, quinine, cinchonidine, ephedrine,α-methylbenzylamine, amphetamine, deoxyphedrine, chloramphenicolintermediate, 2-amino-1-butanol, and 1-(1-napthyl)ethylamine. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules. The synthesizeddiastereoisomers can be separated by conventional means such aschromatography, distillation, crystallization or sublimation, and thenhydrolyzed to deliver the enantiomerically pure compound. The opticallyactive compounds of Formula I can likewise be obtained by utilizingoptically active starting materials. These isomers may be in the form ofa free acid, a free base, an ester or a salt. Additional methods forresolving optical isomers, known to those skilled in the art may beused, for example, those discussed by J. Jaques et al in Enantiomers,Racemates, and Resolutions, John Wiley and Sons, New York (1981).

Also included in the family of compounds of Formula I and I′ are theamide protected acids thereof. Thus primary and secondary amines can bereacted with the chromene-3-carboxylic acids of Formula I and I′ to formamides which can be useful as prodrugs. Preferred aminesheterocyclicamines, including optionally substituted aminothiazoles,optionally substituted amino-isoxazoles, and optionally substitutedaminopyridines; aniline derivatives; sulfonamides; aminocarboxylicacids; and the like. Additionally, 1-acyldihydroquinolines can behave asprodrugs for the 1H-dihydroquinolines.

Also included in the family of compounds of Formula I and I′ are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicyclic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formula I or I′ include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases includingprimary, secondary and tertiary amines, substituted amines includingcyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine,N-ethyl morpholine, piperazine, piperidine, triethylamine,trimethylamine. All of these salts may be prepared by conventional meansfrom the corresponding compound of the invention by reacting, forexample, the appropriate acid or base with the compound of Formula I orI′.

General Synthetic Procedures

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes 1–16, wherein the R¹–R⁶ substituents areas defined for Formulas I–II, above, except where further noted.

Synthetic Scheme 1 illustrates the general method for the preparation ofa wide variety of substituted 2H-1-benzopyran derivatives 3 and 4. Instep 1, a representative ortho-hydroxybenzaldehyde(salicylaldehyde)derivative 1 is condensed with an acrylate derivative 2 in the presenceof base, such as potassium carbonate in a solvent such asdimethylformamide, to afford the desired 2H-1-benzopyran ester 3. Analternative base-solvent combination for this condensation includes anorganic base such as triethylamine and a solvent such as dimethylsulfoxide. In step 2 the ester is hydrolyzed to the corresponding acid,such as by treatment with aqueous base (sodium hydroxide) in a suitablesolvent such as ethanol to afford after acidification the substituted2H-1-benzopyran-3-carboxylic acid 4.

Synthetic Scheme 2 shows the general method for functionalizing selected2H-1-benzopyrans. Treatment of the 2H-1-benzopyran carboxylic acid 4 orester 3 with an electrophillic agent makes a 6-substituted2H-1-benzopyran 5. A wide variety of electrophillic agents reactselectively with 2H-1-benzopyrans 4 in the 6-position to provide newanalogs in high yield. Electrophillic reagents such as halogen (chlorineor bromine) give the 6-halo derivatives. Chlorosulfonic acid reacts toafford the 6-position sulfonyl chloride that can further be converted toa sulfonamide or sulfone. Friedel-Crafts acylation of 4 provides6-acylated 2H-1-benzopyrans in good to excellent yield. A number ofother electrophiles can be used to selectively react with these2H-1-benzopyrans in a similar manner. A 6-position substituted2H-1-benzopyran can react with an electrophilic reagent at the8-position using similar chemistries to that described for electrophilicsubstitution of the 6-position. This yields an 2H-1-benzopyran which issubstituted at both the 6 and 8 positions.

Synthetic Scheme 3 illustrates a second general synthesis of substituted2H-1-benzopyran-3-carboxylic acids which allows substitution at position4 of the 2H-1-benzopyran. In this case a commercially or syntheticallyavailable subtituted ortho-hydroxy acetophenone 6 is treated with two ormore equivalents of a strong base such as lithiumbis(trimethylsilyl)amide in a solvent such as tetrahydrofuran (THF),followed by reaction with diethyl carbonate to afford the beta-ketoester 7. Ester 7 is condensed with an acid chloride or anhydride in thepresence of a base such as potassium carbonate in a solvent such astoluene with heat to afford 4-oxo-4H-1-benzopyran 8. Reduction of theolefin can be accomplished by a variety of agents including sodiumborohydride (NaBH₄) in solvent mixtures such as ethanol andtetrahydrofuran (THF), or by use of triethylsilane in a solvent such astrifluoroacetic acid, or by catalytic reduction using palladium oncharcoal and hydrogen gas in a solvent such as ethanol to yield the newbeta-keto ester 9 (two tautomeric structures shown). Acylation of theoxygen of the ketone enolate in the presence of a base such as2,6-di-tert-butyl-4-methylpyridine, an acylating agent such astrifluoromethanesulfonic anhydride, and using a solvent such asmethylene chloride yields the enol-triflate 10. Triflate 10 can bereduced with reagents such as tri-n-butyltin hydride, lithium chlorideand a palladium (0) catalyst such astetrakis(triphenylphosphine)palladium (0) in a solvent such astetrahydrofuran to yield 2H-1-benzopyran ester 11 where R″ is hydrogen.The ester 11 can be saponified with a base such as 2.5 N sodiumhydroxide in a mixed solvent such as tetrahydrofuran-ethanol-water(7:2:1) to yield the desired substituted 2H-1-benzopyran-3-carboxylicacid.

To incorporate a carbon fragment R³ one can treat triflate 10 withreagents known to undergo “cross-coupling” chemistries such atributylethyenyltin, lithium chloride and a palladium(0) catalyst suchas tetrakis(triphenylphosphine)palladium (0) in a solvent such astetrahydrofuran to yield 2H-1-benzopyran ester 11 where R³ is a vinylmoiety. The ester 6 can be saponified with a base such as 2.5 N sodiumhydroxide in a mixed solvent such as tetrahydrofuran-ethanol-water(7:2:1) to yield the desired 4-vinyl-2H-1-benzopyran-3-carboxylic acid(12, R″═CH₂CH—). Similarly triflate 10 can be converted under similarconditions using tri-n-butylphenyltin to 2H-1-benzopyran where R³=phenyland by hydrolysis of the ester converted to the carboxylic acid 12 whereR³=phenyl. Using a similar strategy, substituents which be incorporatedas substitutent R³ can be substituted olefins, substituted aromatics,substuted heteroaryl, acetylenes and substituted acetylenes.

Synthetic Scheme 4 shows an alternative general procedure for thepreparation of 4-oxo-4H-1-benzopyran 8. Treatment of anortho-fluorobenzoyl chloride with an appropriately substituted beta-ketoester 14 with a base such as potassium carbonate in a solvent such astoluene provides 4-oxo-4H-1-benzopyran 8. 4-oxo-4H-1-benzopyran 8 can beconverted to 2H-1-benzopyran 12 as described in Scheme 3.

Synthetic Scheme 5 shows a general method for substitution of thearomatic ring of the 2H-1-benzopyran. This can be accomplished throughorgano-palladium mediated “cross-coupling” chemistries using a palladium(0) catalyst to couple benzopyran 15 at position Y, where Y is iodide,bromide or triflate, with an acetylene, olefin, nitrile, or arylcoupling agent. Substituted acetylenes as the coupling agent willprovide the corresponding substituted acetylene. Substituted arylmoieties can be incorporated using arylboronic acids or esters; nitritescan be incorporated by use of zinc (II) cyanide. The resulting ester 16can be converted to carboxylic acid 17 as described in Scheme 1.

Another approach to substitution of the aryl moiety of the benzopyran 15is to convert Y, where Y is iodide or bromide, to a perfluoroalkylmoiety. Exemplary of this transformation is the conversion of 15(Y=iodide) to 16 (R^(2′)=pentafluoroethyl) using a potassiumpentafluoropropionate and copper (I) iodide in hexamethylphosphoramide(HMPA). The resulting ester 16 can be converted to carboxylic acid 15 asdescribed in Scheme 1.

A similar method adds substitution of the aromatic ring indihydroquinoline-3-carboxylates. This can be accomplished throughorganopalladium couplings with aryl iodides, bromides, or triflates andvarious coupling agents (R. F. Heck, Palladium Reagents in OrganicSynthesis. Academic Press 1985). When using a suitable palladiumcatalyst such as tetrakis(triphenyl-phospine)palladium(0) in thisreaction, coupling agents such as alkynes provide disubstituted alkynes,phenyl boronic acids afford biphenyl compounds, and cyanides producearylcyano compounds. A number of other palladium catalysts and couplingreagents could be used to selectively react with appropriatelysubstituted dihydroquinoline-3-carboxylates in a similar manner.

Synthetic Scheme 6 shows a general synthetic route for conversion of acommercially or synthetically available substituted phenol into asubstituted salicylaldehyde. Several different methods which utilizeformaldehyde or a chemically equivalent reagent are described in detailbelow.

Reaction of an appropriately substituted phenol 18 in basic media withformaldehyde (or chemical equivalent) will yield the correspondingsalicylaldehyde 1. The intermediate, ortho-hydroxymethylphenol 19, willunder appropriate reaction conditions be oxidized to the salicylaldehyde1 in situ. The reaction commonly employs ethyl magnesium bromide ormagnesium methoxide (one equivalent) as the base, toluene as thesolvent, paraformaldehyde (two or more equivalents) as the source offormaldehyde, and employs hexamethylphoramide (HMPA) orN,N,N′,N′-tetramethylethylenediamine (TMEDA). (See: Casiraghi, G. etal., J. C. S. Perkin I, 1978, 318–321.) Alternatively an appropriatelysubstituted phenol 18 may react with formaldehyde under aqueous basicconditions to form the substituted ortho-hydroxybenzyl alcohol 19 (See:a) J. Leroy and C. Wakselman, J. Fluorine Chem., 40, 23–32 (1988). b) A.A. Moshfegh, et al., Helv. Chim. Acta., 65, 1229–1232 (1982)). Commonlyused bases include aqueous potassium hydroxide or sodium hydroxide.Formalin (38% formaldehyde in water) is commonly employed as the sourceof formaldehyde. The resulting ortho-hydroxybenzyl alcohol 19 can beconverted to the salicylaldehyde 1 by an oxidizing agent such asmanganese (IV) dioxide in a solvent such as methylene chloride orchloroform (See: R-G. Xie, et al., Synthetic Commun. 24, 53–58 (1994)).

An appropriately substituted phenol 18 can be treated under acidicconditions with hexamethylenetetramine (HMTA) to prepare thesalicylaldehyde 1 (Duff Reaction; See: Y. Suzuki, and H. Takahashi,Chem. Pharm. Bull., 31, 1751–1753 (1983)). This reaction commonlyemploys acids such as acetic acid, boric acid, methanesulfonic acid, ortrifluoromethanesulfonic acid. The source of formaldehyde commonly usedis hexamethylenetetramine.

Synthetic Scheme 7 shows the Reimer-Tiemann reaction in which ancommercially or synthetically available appropriately substituted phenol18 will under basic conditions react with chloroform to yield asubstituted salicylaldehyde 1 (See: Cragoe, E. J.; Schultz, E. M., U.S.Pat. No. 3,794,734, 1974).

Synthetic Scheme 8 shows the conversion of a commercially orsynthetically available appropriately substituted salicylic acid 21 toits respective salicylaldehyde 1 via an intermediate 2-hydroxybenzylalcohol 19. Reduction of the salicylic acid 21 can be accomplished witha hydride reducing agent such as borane in a solvent such astetrahydrofuran. Treatment of the intermediate 2-hydroxybenzyl alcohol19 with an oxidizing agent such as manganese (IV) oxide in a solventsuch as methylene chloride or chloroform provides salicylaldehyde 1.

Synthetic Scheme 9 illustrates a general synthetic method forpreparation of a wide variety of substituted2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acids (25). In step1, an appropriately commercially or synthetically available substitutedthiophenol 22 is ortho-metallated with a base such as n-butyllithiumemploying TMEDA (N,N,N′,N′-tetramethylethylenediamine) followed bytreatment with dimethylformamide to provide the 2-mercaptobenzaldehyde23. Condensation of the 2-mercaptobenzaldehyde 23 with an acrylate 2 inthe presence of base provides ester 24 which can be saponified in thepresence of aqueous base to afford the substituted2H-1-benzothiopyran-3-carboxylic acids 25.

Synthetic Scheme 10 shows a method for preparing a substituted2-mercaptobenzaldehyde from an appropriate commercially or syntheticallyavailable substituted salicylaldehyde. In step 1, the phenolic hydroxylof salicylaldehyde 1 is converted to the corresponding O-arylthiocarbamate 26 by acylation with an appropriately substitutedthiocarbamoyl chloride such as N,N-dimethylthiocarbamoyl chloride in asolvent such as dimethylformamide using a base such as triethylamine. InStep 2, O-aryl thiocarbamate 26 rearranges to S-aryl thiocarbamate 27when heated sufficiently such as to 200° C. using either no solvent or asolvent such as N,N-dimethylaniline (See: A. Levai, and P. Sebok, Synth.Commun., 22 1735–1750 (1992)). Hydrolysis of S-aryl thiocarbamate 27with a base such as 2.5 N sodium hydroxide in a solvent mixture such astetrahydrofuran and ethanol yields the substituted2-mercaptobenzaldehyde 23 which can be converted to the substituted2H-1-benzothiopyran-3-carboxylic acids 25 as described in Scheme 9.

Synthetic Scheme 11 illustrates the general method for the preparationof a wide variety of dihydroquinoline-3-carboxylic acid derivatives 30.R² represents the aromatic substitution of commercially andsynthetically available 2-aminobenzaldeydes 28. The 2-amino-benzaldehydederivative 28, where R² represents various substitutions, is condensedwith a acrylate derivative 2 in the presence of base such as potassiumcarbonate, triethylamine, or diazbicyclo[2.2.2]undec-7-ene in solventssuch as dimethylformamide to afford the dihydroquinoline-3-carboxylateesters 29. The ester 29 can be saponified to the corresponding acid,such as by treatment with aqueous inorganic base such as 2.5 N sodiumhydroxide in a suitable solvent such as ethanol to afford afteracidification the desired dihydroquinoline-3-carboxylic acid 30.

Synthetic Scheme 12 illustrates the preparation ofdihydroquinoline-3-carboxylic acid 30 from 2-aminobenzoic acids 31. R²represents the aromatic substitution of commercially and syntheticallyavailable 2-aminobenzoic acids 31. Reduction of the representative2-aminobenzoic acid 31 to the desired 2-aminobenzyl alcohol 32 wasaccomplished with a hydride reducing agent such as borane in a solventsuch as tetrahydrofuran. Treatment of the desired 2-aminobenzyl alcohol32 with an oxidizing agent such as manganese(IV)oxide in a solvent suchas methylene chloride provides the representative 2-aminobenzaldehydes28. (C. T. Alabaster, et al. J. Med. Chem. 31, 2048–2056 (1988)) The2-aminobenzaldehydes were converted to the desireddihydroquinoline-3-carboxylic acid 30 as described in Scheme 11.

Synthetic Scheme 13 illustrates the general method for the preparationof a wide variety of dihydroquinoline-3-carboxylic acid derivatives 30from isatins 33. R² represents the aromatic substitution of commerciallyand synthetically available isatins 33. A representative isatin 33 wastreated with basic peroxide generated from hydrogen peroxide and a basesuch as sodium hydroxide to afford the desired representative2-aminobenzoic acids 31. (M. S. Newman and M. W. Lougue, J. Org. Chem.,36, 1398–1401 (1971)) The 2-aminobenzoic acids 31 are subsequentlyconverted to the desired dihydroquinoline-3-carboxylic acid derivatives30 as described in synthetic Scheme 12.

Synthetic Scheme 14 is another general method for the preparation ofdihydroquinoline-3-carboxylic acid derivatives 30. In step 1, anappropriate commercially or synthetically available substituted aniline34 can be treated with an acylating reagent such as pivaloyl chlorideyielding an amide 35. The ortho-dianion of amide 35 is prepared bytreating amide 35 with organo-lithium bases such as n-butyllithium ortert-butyllithium in tetrahydrofuran at low temperature. The dianion isquenched with dimethylformamide to afford theacylated-2-amino-benzaldehydes 36. (J. Turner, J. Org. Chem., 48,3401–3408 (1983)) Reaction of these aldehydes in the presence of basessuch as lithium hydride with a acrylate followed by work up with aqueousinorganic bases and hydrolysis, such as by treatment with aqueous base(sodium hydroxide) in a suitable solvent such as ethanol affords, afteracidification, a dihydroquinoline-3-carboxylic acid 30.

Synthetic Scheme 15 shows a general method for alkylation of thenitrogen of dihydroquinoline-3-carboxylate ester derivatives 29. Thestep involves treatment of dihydroquinoline-3-carboxylate esterderivatives 29 with alkyl halides such as iodoethane in the presence ofphase transfer catalysts such a tetrabutylammonium iodide, and a basesuch as caustic (50% aqueous sodium hydroxide) in a solvent such asdichloromethane. These conditions afford the N-alkylateddihyrdoquinoline-3-carboxylate esters 37. Saponification of 37 withaqueous base provides N-alkylated-dihyroquinoline-3-carboxylic acidderivatives 38.

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formulas I–II. These detailed descriptionsfall within the scope, and serve to exemplify, the above describedGeneral Synthetic Procedures which form part of the invention. Thesedetailed descriptions are presented for illustrative purposes only andare not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. All compounds showed NMR spectra consistent withtheir assigned structures.

The following abbreviations are used:

-   HCl—hydrochloric acid-   MgSO₄—magnesium sulfate-   Na₂SO₄—sodium sulfate-   DMF—dimethylformamide-   THF—tetrahydrofuran-   NaOH—sodium hydroxide-   EtOH—ethanol-   K₂CO₃—potassium carbonate-   CDCl₃—deuterated chloroform-   CD₃OD—deuterated methanol-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   NaHCO₃—sodium bicarbonate-   KHSO₄—potassium sulfate-   NaBH₄—sodium borohydride-   TMEDA—tetrametylethylenediamine-   HMTA—hexamethylenetetraamine-   DMSO—dimethyl sulfoxide-   HMPA hexamethyl phosphoric triamide

EXAMPLE 1

6-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

A mixture of 5-chlorosalicylaldehyde (20.02 g, 0.128 mole) and ethyl4,4,4-trifluorocrotonate (23.68 g, 0.14 mole) was dissolved in anhydrousDMF, warmed to 60° C. and treated with anhydrous K₂CO₃ (17.75 g, 0.128mole). The solution was maintained at 60° C. for 20 hours, cooled toroom temperature, and diluted with water. The solution was extractedwith ethyl acetate. The combined extracts were washed with brine, driedover anhydrous MgSO₄, filtered and concentrated in vacuo to afford 54.32g of an oil. The oil was dissolved in 250 mL of methanol and 100 mL ofwater, whereupon a white solid formed that was isolated by filtration,washed with water and dried in vacuo, to afford the ester as a yellowsolid (24.31 g, 62%): mp 62–64° C. ¹H NMR (CDCl₃/90 MHz) 7.64 (s, 1H),7.30–7.21 (m, 2H), 6.96 (d, 1H, J=Hz), 5.70 (q, 1H, J=Hz), 4.30 (q, 2H,J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).

Step 2. Preparation of6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

A solution of the ester from Step 1 (13.02 g, 42 mmole) was dissolved in200 mL of methanol and 20 mL of water, treated with lithium hydroxide(5.36 g, 0.128 mole) and stirred at room temperature for 16 hours. Thereaction mixture was acidified with 1.2 N HCl, whereupon a solid formedthat was isolated by filtration. The solid was washed with 200 mL ofwater and 200 mL of hexanes and dried in vacuo to afford the titlecompound as a yellow solid (10.00 g, 85%): mp 181–184° C.

EXAMPLE 2

6-(Methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of 5-(methylthio)salicylaldehyde.

Ethyl magnesium bromide (38 mL of a 3.0 M solution in diethyl ether,113.8 mmole) was chilled with an ice-water bath. To the chilled solutionwas added a solution of 4-(methylthio)phenol (15.95 g, 113.8 mmole) indiethyl ether (30 mL) over 0.15 hour during which time gas was evolved.The reaction was held at 0° C. for 0.5 hour, at room temperature for 0.5hour, and the addition funnel replaced with a distillation head. Toluene(250 mL) and the diethyl ether were distilled out of the reactor. Thereaction was cooled, toluene (250 mL) and hexamethylphosphoramide (HMPA)(19.8 mL, 20.4 g, 113.8 mmole) were added, and the resulting mixture wasstirred for 0.25 hours. The distillation head was replaced with acondenser and paraformaldehyde (8.5 g, 284.4 mmole) was added. Thereaction was heated to 90° C. for 3 hours. The reaction mixture wascooled to room temperature, was acidified with 1N HCl and the layersseparated. The organic phase was washed with water, and with brine,dried over MgSO₄, filtered, and concentrated in vacuo to yield a solid.This solid was purified by silica chromatography (hexanes-ethyl acetate,5:1) yielding the salicylaldehyde as a yellow crystalline solid (6.01 g)of suitable purity to be used in the next reaction without furtherpurification.

Step 2. Preparation of ethyl6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

5-Methylthiosalicylaldehyde (Step 1) (2.516 g, 14.96 mmole) was added todimethylformamide (3.5 mL), potassium carbonate (2.27 g, 16.45 mmole)and ethyl 4,4,4-trifluorocrotonate (3.3 mL, 3.8 g, 22.4 mmole). Themixture was heated to 65° C. for 3 h. The reaction was cooled to roomtemperature, poured into H₂O (50 mL), and extracted with diethyl ether(2×75 mL). The combined ethereal phases were washed with aqueous NaHCO₃solution (3×50 mL), aqueous 2 N HCl solution (3×50 mL), and brine (3×50mL), dried over MgSO₄, filtered, diluted with isooctane and partiallyconcentrated in vacuo causing the precipitation of the ethyl ester(2.863 g, 60%) as a yellow powder: mp 87.8–89.6° C. This ester was ofsuitable purity to use without further purification.

Step 3. Preparation of6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

The ester (Step 2) was hydrolyzed to form the carboxylic acid via amethod similar to that described in Example 1, Step 2: mp 166.3–167.9°C. ¹H NMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.43 (d, 1H, J=2.2 Hz),7.33 (dd, 1H, J=8.5, 2.4 Hz), 6.98 (d, 1H, J=8.5 Hz), 5.79 (q, 1H, J=7.0Hz), 2.48 (s, 3H). FABLRMS m/z 291 (M+H). ESHRMS m/z 289.0152 (M−H,Calc'd 289.0146). Anal. Calc'd for C₁₂H₉F₃O₃S₁: C, 49.66; H, 3.13; S,11.05. Found: C, 49.57; H, 3.02; S, 11.37.

EXAMPLE 3

7-Methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3-Methylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 202.1–203.1° C. ¹H NMR(CDCl₃/300 MHz) 7.84 (s, 1H), 7.12 (d, 1H, J=8.3 Hz), 6.82 (m, 2H), 5.65(q, 1H, J=6.8 Hz), 2.35 (s, 3H). FABLRMS m/z 259 (M+H). FABHRMS m/z259.0576 (M+H, Calc'd 259.0582). Anal. Calc'd for C₁₂H₉F₃O₃: C, 55.82;H, 3.51. Found: C, 55.93; H, 3.59.

EXAMPLE 4

2,7-bis(Trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

3-(Trifluoromethyl)phenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 190.3–193.5° C. ¹HNMR (acetone-d₆/300 MHz) 7.98 (s, 1H), 7.73 (d, 1H, J=7.9 Hz), 7.46 (d,1H, J=7.9 Hz), 7.36 (s, 1H), 5.93 (q, 1H, J=7.1 Hz). FABLRMS m/z 313(M+H). FABHRMS m/z 313.0267 (M+H, Calc'd 313.0299). Anal. Calc'd forC₁₂H₆F₆O₃: C, 46.17; H, 1.94. Found: C, 46.25; H, 2.00.

EXAMPLE 5

7-Bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3-Bromophenol was converted to the title compound by a procedure similarto that described in Example 2: mp 198.4–199.5° C. ¹H NMR(acetone-d₆/300 MHz) 7.89 (s, 1H), 7.43 (d, 1H, J=8.1 Hz), 7.31 (s, 1H),7.30 (d, 1H, J=8.1 Hz), 5.84 (q, 1H, J=7.1 Hz). FABLRMS m/z 323 (M+H).Anal. Calc'd for C₁₁H₆BrF₃O₃: C, 40.90; H, 1.87. Found: C, 41.00; H,.1.85.

EXAMPLE 6

6-Chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-Chloro-3-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 207.5–209.3° C. ¹HNMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.23 (s, 1H), 6.90 (s, 1H), 5.65 (q,1H, J=6.8 Hz), 2.37 (s, 3H). FABLRMS m/z 292 (M+H). FABHRMS m/z 299.0287(M+Li, Calc'd 299.0274). Anal. Calc'd for C₁₂H₈ClF₃O₃: C, 49.25; H,2.76; Cl, 12.11. Found: C, 49.37; H, 2.82; Cl, 12.17.

EXAMPLE 7

6-(4-Methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

4-(4-Methoxyphenyl)phenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 181.7–182.9° C. ¹HNMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.11 (m, 1H), 7.02 (m, 2H), 6.98(m, 4H), 5.81 (q, 1H, J=7.0 Hz), 3.80 (s, 3H). FABLRMS m/z 365 (M−H).FABHRMS m/z 367.0809 (M+H, Calc'd 367.0793). Anal. Calc'd forC₁₈H₁₃F₃O₅: C, 59.02; H, 3.58. Found: C, 59.10; H, 3.61.

EXAMPLE 8

6-Chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of 4-tert-butylsalicylaldehyde.

A five liter three-neck round bottom flask equipped with overheadmechanical stirrer and condenser was charged with trifluoroacetic acid(2.4 L). A mixture of 3-tert-butylphenol (412 g, 2.8 mole) and HMTA (424g, 3.0 mole) was added portion-wise causing an exotherm. With cooling,the temperature was maintained under 80° C. The reaction was heated at80° C. for one-hour, then cooled, and water (2 L) added. After 0.5 houradditional water (4 L) was added and the mixture was extracted withethyl acetate (6 L). The organic extract was washed with water andbrine. The resulting organic phase was divided into 2 L volumes and eachdiluted with water (1 L), and solid NaHCO₃ added until the mixture wasneutralized. The organic phases were isolated and combined, dried overMgSO₄, filtered and concentrated in vacuo yielding an oil. This oil wasdistilled at 95° C. (0.8 mm) yielding the desired salicylaldehyde as anoil (272.9 g, 56%) which was of sufficient purity to be used withoutfurther purification.

Step 2. Preparation of ethyl7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A one liter three-neck flask was charged with4-tert-butylsalicylaldehyde (Step 1)(100.0 g, 0.56 mole),dimethylformamide (110 mL), and potassium carbonate (79.9 g, 0.58 mole)causing the temperature of the mixture to rise to 40° C. Ethyl4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethylformamide (110mL) was added and the mixture heated to 60° C. at which time thereaction temperature rose to 70° C. The reaction was cooled to 60° C.,maintained at 60° C. (with added heating) for 8.5 hours and cooled toroom temperature. Ethyl acetate (600 mL) and 3 N HCl (600 mL) wereadded, mixed, and the layers separated. The aqueous phase was extractedwith ethyl acetate and the organic phases were combined. The combinedorganic phases were washed with brine-water (1:1), brine, dried overMgSO₄, filtered and concentrated in vacuo, yielding a semi-solid. Hexane(600 mL) was added with mixing and the mixture was filtered. Thefiltrate was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo yielding a solid. This solid was dissolved in hotethanol (600 mL). Water (190 mL) was added which inducedcrystallization. Filtration of the mixture and drying of the productprovided the desired ester as a crystalline solid (131.3 g, 71%): mp91.0–94.9° C. This material was of suitable purity to be used insubsequent steps without further purification.

Step 3. Preparation of ethyl6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A one liter three-neck flask equipped with mechanical stirrer and gasinlet tube was charged with the ester (Step 2) (100 g, 0.3 mole) andacetic acid (300 mL). While cooling (water bath) the reaction mixture,chlorine gas (37.6 g, 0.53 mole) was added which caused the temperatureto rise to 48° C. After stirring for two hours, the reaction was cooledin an ice-water bath to 15° C. Zinc powder (19.5 g, 0.3 mole) was addedin one portion which caused the temperature to rise to 72° C. Aftercooling to room temperature additional zinc powder (5.0 g, 0.08 mole)was added and the mixture was stirred for 0.5 hour longer. The crudemixture was filtered through diatomaceous earth and was concentrated invacuo yielding an oil. The oil was dissolved in ethyl acetate (700 mL)washed with brine-water (1:1, 1 L) and brine (0.5 L). The resultingaqueous phase was extracted with ethyl acetate (700 mL). This ethylacetate phase was washed with brine-water (1:1, 1 L) and brine (0.5 L).The combined organic phases were dried over MgSO₄, filtered andconcentrated in vacuo yielding the title compound as a yellow oil (116g, 106%). This material, which contained some entrained ethyl acetate,was of suitable purity to be used in subsequent steps without furtherpurification.

Step 4. Preparation of6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

To a solution of the ester (Step 3) (116 g, 0.3 mole) in methanol (500mL) and tetrahydrofuran (500 mL) in a one liter flask was added aqueoussodium hydroxide (2.5 N, 240 mL, 0.6 mole). After stirring overnight,the pH of the solution was adjusted to 1 with concentrated hydrochloricacid and the solution was extracted with ethyl acetate. The ethylacetate phase was dried over MgSO₄, filtered and concentrated in vacuoyielding a solid. This solid was dissolved in hot ethanol (500 mL).Water (500 mL) was added and upon cooling to room temperature crystalsformed which were collected by vacuum filtration. The crystals werewashed with ethanol-water (3:7, 3×200 mL) and dried providing the titleacid as a crystalline solid (91.6 g, 91%): mp 194.9–196.5° C. ¹H NMR(acetone-d₆/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 5.83 (q,1H, J=7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C₁₅H₁₄ClF₃O₃: C, 53.83; H,4.22; Cl, 10.59. Found: C, 53.92; H, 4.24; Cl, 10.50.

EXAMPLE 9

6-(3-Chloro-4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

To a stirred solution of chlorine in acetic acid (3.5 mL of 0.24 Msolution, 0.84 mmol) was added6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid (0.31 g, 0.85 mmol) (Example 7). After 1 hour additional chlorinein acetic acid (1.5 mL of 0.24 M solution, 0.36 mmol) was added. Afterthree additional hours additional chlorine in acetic acid (0.25 ml of0.25 M solution, 0.06 mmol) was added. After 2.5 hours the reaction wasquenched with aqueous 10% sodium bisulfite solution and the resultingmixture extracted with ethyl acetate. The organic phase was washed withwater, brine, dried over MgSO₄, filtered, and concentrated in vacuoyielding a brown oil. The oil was dissolved in a minimum of hexaneswhich induced crystallization. Vacuum filtration of the mixture providedthe title compound as yellow crystals (0.18 g, 53%): mp 205–207° C. ¹HNMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 6.97–7.18 (m, 6H), 5.83 (q, 1H,J=7.0 Hz), 3.90 (s, 3H). FABLRMS m/z 400 (M+). FABHRMS m/z 399.0249(M−H, Calc'd 399.0247). Anal. Calc'd for C₁₈H₁₂ClF₃O₅: C, 53.95; H,3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl, 8.98.

EXAMPLE 10

2-Trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

The ester was prepared from salicylaldehyde by a procedure similar tothe method described in Example 1, Step 1: bp 107° C. 2 mm. ¹HNMR(acetone-d₆/300 MHz) 7.89 (s, 1H), 7.52–7.38 (m, 2H), 7.09 (dt, 1 J=1.0,7.7 Hz), 7.03 (d, 1H, J=8.3 Hz), 5.84 (q, 1H, J=7.3 Hz), 4.39–4.23 (m,2H), 1.33 (t, 3H, J=7.0 Hz). FABLRMS m/z 273 (M+H). ESHRMS (m/z 273.0720(M+H Calcd 273.0739)

Step 2. Preparation of 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

The acid was prepared from the ethyl ester (Step 1) by a proceduresimilar to the method described in Example 1, Step 2: mp 152.2–153.3° C.¹H NMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 7.39–7.49 (m, 2H), 7.11–7.01(m, 2H), 5.81 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 245.0422 (M+H, Calc'd245.0426). Anal. Calc'd for C₁₁H₇F₃O₃: C, 54.11; H, 2.89. Found: C,54.22; H, 2.97.

EXAMPLE 11

6,8-Dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of 3,5-dichloro-4-methylsalicylaldehyde.

2,4-Dichloro-3-methylphenol (25.0 g, 141.2 mmol) was added tomethanesulfonic acid (100 mL). With stirring, hexamethylenetetramine(HMTA) (39.8 g, 282.4 mmol) and additional methanesulfonic acid (100 mL)was added portion-wise during which time the reaction began to froth andexotherm. The resulting mixture was heated to 100° C. for 3 hours. Thecrude ocher colored suspension was cooled to 50° C. and poured over amechanically stirred mixture of ice-water (2 L). A yellow precipitatewas formed which was collected by vacuum filtration. This solid waspurified by flash chromatography (silica, hexanes-methylene chloride,9:10) yielding the salicylaldehyde as a pale yellow powder (6.17 g, 21%;mp 94.0–95.1° C.) of suitable purity to use without furtherpurification.

Step 2. Preparation of ethyl6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A mixture of 3,5-dichloro-4-methylsalicylaldehyde (Step 1) (5.94 g, 29.0mmol) and ethyl 4,4,4-trifluorocrotonate (7.67 g, 45.6 mmol) dissolvedin anhydrous DMSO (10 mL) was treated with triethylamine (5.88 g, 58.1mmol). The reaction was stirred at 85° C. for 49 hours then cooled inice and filtered to give an orange solid. The solid was dissolved inethyl acetate (100 mL), washed with 3 N HCl (2×50 mL), saturated NaHCO₃,washed with brine, dried over MgSO₄, and concentrated in vacuo to give ayellow solid (8.63 g, 84%): mp 117.1–119.5° C. ¹H NMR (CDCl₃/300 MHz)7.63 (s, 1H), 7.17 (s, 1H), 5.80 (q, 1H, J=6.6 Hz), 4.33 (m, 2H), 2.48(s, 3H), 1.35 (t, 3H, J=7.1 Hz).

Step 3. Preparation of6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

The ester from Step 2 (8.39 g 23.6 mmol) was dissolved in THF (30 mL)and ethanol (20 mL), treated with 2.5 N sodium hydroxide (20 mL, 50mmol), and stirred at room temperature for 3.5 hours. The reactionmixture was concentrated in vacuo, acidified with 3 N HCl, filtered, andrecrystallized from ethanol/water to yield a yellow solid (6.0 g, 78%):mp 229.9–230.9° C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.58 (s,1H), 6.00 (q, 1H, J=6.8 Hz), 2.50 (s, 3H). FABLRMS m/z 325 (M−H).FABHRMS m/z 324.9636 (M−H, Calc'd 324.9646). Anal. Calc'd forC₁₂H₇Cl₂F₃O₃: C, 44.07; H, 2.16; Cl, 21.68. Found: C, 44.06; H, 2.21;Cl, 21.74.

EXAMPLE 12

7-(1,1-Dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

Ethyl7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 8, Step 2) was hydrolyzed to the carboxylic acid via aprocedure similar to that described in Example 1, Step 2: mp165.6–166.8° C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.38 (d, 1H,J=8.1 Hz), 7.15 (dd, 1H, J=1.8 Hz, and J=7.8 Hz), 7.05 (bs, 1H), 5.79(q_(H-F), 1H, J=7.2 Hz), 1.32 (s, 9H). FABHRMS m/z 301.1033 (M+H, Calc'd301.1051). Anal. Calc'd for C₁₅H₁₅F₃O₃: C, 60.00; H, 5.04. Found: C,59.80; H, 5.10.

EXAMPLE 13

6-Bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

5-Bromosalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 189.6–190.9° C. ¹HNMR (acetone-d₆/300 MHz) 7.89 (s, 1H), 7.70 (d, 1H, J=2.1 Hz), 7.55 (dd,1H, J=2.4 Hz, and J=8.7 Hz), 7.02 (d, 1H, J=8.7 Hz), 5.86 (q_(H-F), 1H,J=7.2 Hz). FABHRMS m/z 322.9519 (M+H, Calc'd 322.9531). Anal. Calc'd forC₁₁H₆BrF₃O₃: C, 40.90; H, 1.87; Br, 24.73. Found: C, 40.87; H, 1.92; Br,24.80.

EXAMPLE 14

8-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Chlorophenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 224.5–225.6° C. ¹H NMR(acetone-d₆/300 MHz) 7.91 (s, 1H), 7.49 (m, 2H), 7.11 (t, 1H, J=7.8 Hz),5.96 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 279.0027 (M+H, Calc'd279.0036). Anal. Calc'd for C₁₁H₆ClF₃O₃: C, 47.42; H, 2.17. Found: C,47.33; H, 2.17.

EXAMPLE 15

8-Bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Bromo-4-chlorosalicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 1: mp 227.8–228.9° C. ¹HNMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H, J=2.4 and J=28.8Hz), 6.00 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 356.9134 (M+H, Calc'd356.9141). Anal. Calc'd for C₁₁H₅BrClF₃O₃: C, 36.96; H, 1.41. Found: C,37.05; H, 1.33.

EXAMPLE 16

6-Trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

5-(Trifluoromethoxy)salicylaldehyde was converted to the title compoundby a similar procedure to that described in Example 1: mp 118.4–119.5°C. ¹H NMR (acetone-d₆/300 MHz) 7.95 (s, 1H), 7.54 (d, 1H, J=2.1 Hz),7.39 (dd, 1H, J=2.4 Hz, and J=9.0 Hz), 7.02 (d, 1H, J=9.0 Hz), 5.88(q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 329.0228 (M+H, Calc'd 329.0249).Anal. Calc'd for C₁₂H₆F₆O₄: C, 43.92; H, 1.84. Found: C, 43.84; H, 1.87.

EXAMPLE 17

8-Fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3-Fluorosalicylaldehyde was converted to the title compound by a similarprocedure to that described in Example 1: mp 197.7–210.1° C. ¹H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.30 (m, 2H), 7.11 (m 1H), 5.93(q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 263.0341 (M+H, C₁₁H₆F₄O₃ Calc'd263.0331). Anal. Calc'd for C₁₁H₆F₄O₃: C, 50.40; H, 2.31. Found: C,50.48; H, 2.25.

EXAMPLE 18

5,7-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4,6-Dichlorosalicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 1: mp 190.1–191.2° C. ¹HNMR (acetone-d₆/300 MHz) 8.01 (s, 1H), 7.3 (bs, 1H), 7.16 (bs, 1H), 5.94(q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 312.9636 (M+H, Calc'd 312.9646).Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C, 42.20; H, 1.61. Found: C, 42.27; H,1.56.

EXAMPLE 19

7,8-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3,4-Dichlorophenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 219.5–220.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.51 (d, 1H, J=8.4 Hz), 7.34 (d, 1H,J=8.4 Hz), 6.02 (q_(H-F), 1H, J=7.2. Hz). FABHRMS m/z 318.9709 (M+Li,C₁₁H₅Cl₂F₃O₃ Calc'd 318.9728). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C, 42.20;H, 1.61. Found: C, 42.15; H, 1.68.

EXAMPLE 20

7-Isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2,4-Dihydroxybenzaldehyde was alkylated to prepare4-(1-methylethyloxy)salicylaldehyde. This salicylaldehyde was convertedto the title compound by a similar procedure to that described inExample 1: mp 161–163° C. ¹H NMR (CD₃OD/300 MHz) 7.73 (s, 1H), 7.21 (d,1H, J=8.5 Hz), 6.57 (dd, 1H, J=8.5, 2.2 Hz). FABHRMS m/z 301.0688 (M−H⁺,C₁₁H₁₂F₃O₄ requires 301.0687). Anal. Calc'd for C₁₁H₁₃F₃O₄: C, 55.63; H,4.34. Found: C, 55.72; H, 4.34.

EXAMPLE 21

8-Phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Phenylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 171.6–175.0° C. ¹H NMR(acetone-d₆/300 MHz) 7.95 (s, 1H), 7.46 (m, 7H), 7.18 (t, 1H, J=7.5 Hz),5.81 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 327.0816 (M+Li, Calc'd327.0820). Anal. Calc'd for C₁₇H₁₁F₃O₃: C, 63.76; H, 3.46. Found: C,63.52; H, 3.55.

EXAMPLE 22

7,8-Dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2,3-Dimethylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 245.2–247.3° C. ¹H NMR(acetone-d₆/300 MHz) 7.83 (s, 1H), 7.17 (d, 1H, J=7.8 Hz), 6.89 (d, 1H,J=7.8 Hz), 5.82 (q_(H-F), 1H, J=7.2 Hz), 2.30 (s, 3H), 2.17 (s, 3H).Anal. Calc'd for C₁₃H₁₁F₃O₃+1.56% H₂O: C, 56.46; H, 4.18. Found: C,56.46; H, 4.15.

EXAMPLE 23

6,8-bis(1,1-Dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3,5-Di-tert-butylsalicylaldehyde was converted to the title compound bya similar procedure to that described in Example 1: mp 171.6–175.0° C.¹H NMR (acetone-d₆/300 MHz) 7.65 (s, 1H), 7.34 (d, 1H, J=2.4 Hz), 7.15(d, 1H, J=2.4 Hz), 6.02 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 363.1743(M+Li, Calc'd 363.1759). Anal. Calc'd for C₁₉H₂₃BrF₃O₃: C, 64.03; H,6.50. Found: C, 64.13; H, 6.49.

EXAMPLE 24

6-Iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Step 1: Preparation of 2-hydroxy-5-iodobenzyl alcohol.

A solution of 5-iodosalicylic acid (25.0 g, 94.6 mmol) intetrahydrofuran (500 mL) was cooled to 0° C. With vigorous mixing,borane-methyl sulfide complex (15.1 ml of 10 M solution, 151.0 mmol) wasadded drop-wise over 0.25 hours. The solution was warmed to roomtemperature and then heated at reflux for 4 h. A white precipitateformed during the reflux. The solution was cooled to room temperatureand 10% aqueous hydrochloric acid (100 mL) was added over 15 min and thesolution stirred at room temperature for 2 h. The precipitate dissolvedand the solvent was concentrated in vacuo to a volume of approximately200 mL. The solution was poured into ethyl acetate (300 mL) and washedwith water (2×200 mL), saturated sodium bicarbonate (2×00 mL), andsaturated ammonium chloride (2×200 mL). The organic layer was dried oversodium sulfate and concentrated in vacuo. The 2-hydroxy-5-iodobenzylalcohol was isolated as a white solid (21.3 g, 85.2 mmol)from hexanes.(90% yield): mp 105–110° C. ¹H NMR (CDCl₃/300 MHz) 8.21 (s, 1H),7.30–7.33 (M, 2H), 6.57 (d, 1H, J=8.3 Hz), 4.97 (bs, 1H), 4.62 (s, 2H).EIHRMS m/z=249.9492 (M+, Calc'd 249.9491).

Step 2: Preparation of 2-hydroxy-5-iodobenzaldehyde.

To a stirred solution of 2-hydroxy-5-iodobenzyl alcohol (43.5 g, 174.0mmol) in acetone (700 mL) was added 85% activated manganese(IV) oxide (5micron, 50 g, 494.0 mmol) and the solution stirred at room temperaturefor 16 hours. The manganese oxide was removed by filtration throughdiatomaceous earth and the filtrate concentrated in vacuo. The productwas purified by flash silica chromatography (0–20% ethyl acetate inhexanes) The 2-hydroxy-5-iodobenzaldehyde was obtained as agreenish-yellow solid (24.3 g, 58%). A small amount of the2-hydroxy-5-iodobenzaldehyde was recrystallized from methanol/water toafford an analytical sample and the remainder of the compound was usedwithout further purification: mp 99–101° C. ¹H NMR (CDCl₃/300 MHz) 9.83(s, 1H), 7.79 (d, 1H, J=2.2 Hz), 7.77 (dd, 1H, J=8.7 Hz, J=2.2 Hz), 6.81(d, 1H, J=8.7 Hz). ESHRMS 246.9229 (M−H Calc'd 246.9256).

Step 3: Preparation of ethyl6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

A mixture of 5-iodosalicylaldehyde (16.2 g, 65.3 mmol), ethyl4,4,4-trifluorocrotonate (22.4 g, 133 mmol) and triethylamine (50 ml,395 mmol)were combined, stirred at 70° C. for 8 h and then heated atreflux for 48 h. The solution was poured into ethyl acetate (300 mL) andwashed with 1N hydrochloric acid (3×200 mL). The aqueous layers werecombined and extracted with ethyl acetate (1×100 mL). The combined ethylacetate extracts were washed with saturated ammonium chloride (2×200mL), dried over magnesium sulfate and concentrated in vacuo yielding adark red oil. This oil was purified by flash chromatography using ethylacetate-hexanes (3:7) yielding a red oil. Crystallization of this oilfrom hexanes yielded the title compound as light red crystals (8.3 g,31%): mp 105–106° C. ¹H NMR (CDCl₃/300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H,J=8.6, J=2.1 Hz, 7.54 (d, 1H, J=2.1 Hz), 6.77 (d, 1H, J=8.6 Hz), 5.70(q, 1H, J=6.7 Hz), 4.20–4.38 (m 2H), 1.35 (t, 3H, J=7.2 Hz). ESHRMS415.9926 (M+NH4⁺ Calc'd 396.9746)

Step 4: Prepartation of6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

Hydrolysis of the ester (Step 3), using a procedure similar to Example1, Step 2, yielded the carboxylic acid: mp 168–170° C. ¹H NMR (CD₃OD/300MHz) 7.57 (s, 1H), 7.70 (d, 1H, J=2.2 Hz), 7.64 (dd, 1H, J=8.5, 2.2 Hz),6.79 (d, 1H, J=8.5 Hz) 5.78 (q, 1H, J=7.0 Hz). ESHRMS m/z 368.9222(Calc'd for M−H 368.9235). Anal. Calc'd for C₁₁H₆F₃IO₃: C, 35.70; H,1.63. Found C, 35.67; H, 1.63.

EXAMPLE 25

7-(1-Methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3-(1-Methylethyl)phenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 158.3–159.7° C. ¹HNMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.37 (d, 1H, J=7.8 Hz), 7.00 (d,1H, J=7.8 Hz), 6.91 (s, 1H), 5.78 (q, 1H, J=6.9 Hz), 2.93 (m, 1H), 1.24(d, 6H, J=6.9 Hz). FABLRMS m/z 287 (M+H). Anal. Calc'd for C₁₄H₁₃F₃O₃:C, 58.74; H, 4.58. Found: C, 57.37; H, 4.49.

EXAMPLE 26

7-Phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3-Phenylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 209.4–211.7° C. ¹H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.74 (m, 2H), 7.47 (m, 5H), 7.33 (s,1H), 5.86 (q, 1H, J=7.2 Hz). FABLRMS m/z 321 (M+H). Anal. Calc'd forC₁₇H₁₁F₃O₃: C, 63.76; H, 3.46. Found: C, 64.17; H, 3.61.

EXAMPLE 27

6-Chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-Chloro-3-ethylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 170.7–172.1° C. ¹HNMR (CDCl₃/300 MHz) 7.78 (s, 1H), 7.26 (s, 1H), 6.90 (s, 1H), 5.67 (q,1H, J=6.9 Hz), 2.73 (q, 2H, J=7.8 Hz), 1.24 (t, 3H, J=7.8 Hz). FABLRMSm/z 307 (M+H). Anal. Calc'd for C₁₃H₁₀F₃O₃: C, 50.92; H, 3.29. Found: C,51.00; H, 3.33.

EXAMPLE 28

8-Ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Ethylphenol was converted to the title compound by a procedure similarto that described in Example 2: mp 185.4–186.8° C. ¹H NMR(acetone-d₆/300 MHz) 7.85 (s, 1H), 7.28 (d, 2H, J=7.5 Hz), 7.00 (t, 1H,J=7.5 Hz), 5.84 (q, 1H, J=7.2 Hz), 2.65 (m, 2H), 1.18 (t, 3H, J=7.5 Hz).FABLRMS m/z 273 (M+H). Anal. Calc'd for C₁₃H₁₁F₃O₃: C, 57.36; H, 4.07.Found: C, 57.15; H, 4.11.

EXAMPLE 29

6-Chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

8-Ethyl-2-(trifluoromethyl)2H-1-benzopyran-3-carboxylic acid (Example28) (0.68 g, 2.5 mmol) was dissolved in trimethylphosphate (5 mL) andwas treated with sulfuryl chloride (0.35 g, 2.62 mmol) at 0° C. Afterstirring at 0° C. for 45 minutes and 1 hour at room temperature, thereaction was diluted with cold water (15 mL). The resulting oily mixturewas extracted with hexanes-ethyl acetate. The organic phase was washedwith brine, dried, and concentrated in vacuo yielding the title compoundas a solid (0.9 g, 117%): mp 197.2–199.1° C. ¹H NMR (acetone-d₆/300 MHz)7.86 (s, 1H), 7.38 (d, 1H, J=2.7 Hz), 7.30 (d, 1H, J=2.4 Hz), 5.88 (q,1H, J=7.2 Hz), 2.65 (m, 2H), 1.19 (t, 3H, J=7.5 Hz). FABLRMS m/z 307(M+H). Anal. Calc'd for C₁₃H₁₀ClF₃O₃: C, 50.92; H, 3.29. Found: C,51.00; H, 3.23.

EXAMPLE 30

6-Chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

7-Phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example26) was converted to the title compound by a procedure similar to thatdescribed in Example 29: mp 185.3–187.8° C. ¹H NMR (acetone-d₆/300 MHz)7.94 (s, 1H), 7.68 (s, 1H), 7.47 (m, 5H), 7.06 (s, 1H), 5.87 (q, 1H,J=6.9 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C₁₇H₁₀ClF₃O₃: C,57.56; H, 2.84. Found: C, 58.27; H, 3.11.

EXAMPLE 31

6,7-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3,4-Dichlorophenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 196.1–198.3° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.74 (s, 1H), 7.30 (s, 1H), 5.88 (q,1H, J=6.9 Hz). FABLRMS m/z 314 (M+H). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C,42.20; H, 1.61. Found: C, 42.31; H, 1.65.

EXAMPLE 32

6,8-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3,5-Dichlorosalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 11, Steps 2 & 3: mp212.8–216.8° C. ¹H NMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.41 (d, 1H, J=2.4Hz), 7.18 (d, 1H, J=2.2 Hz), 5.82 (q, 1H, J=6.7 Hz). FABLRMS m/z 311(M−H). FABHRMS m/z 312.9644 (M+H, Calc'd 312.9646). Anal. Calc'd forC₁₁H₅F₃Cl₂O₃: C, 42.20; H, 1.61. Found: C, 42.50; H, 1.71.

EXAMPLE 33

6,8-Dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3,5-Dibromosalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 225–226° C. ¹H NMR(CD₃OD/300 MHz) 7.76 (s, 1H), 7.74 (d, 1H, J=2.2 Hz), 7.55 (d, 1H, J=2.2Hz), 5.91 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 400.8648 (M+H⁺, Calc'd400.8636). Anal. Calcd for C₁₁H₅Br₂F₃O₃: C, 32.87; H, 1.25. Found: C,33.47; H, 1.38.

EXAMPLE 34

6,8-Dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4,6-Dimethoxysalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 215–217° C. ¹H NMR(CD₃OD/300 MHz) 7.95 (s, 1H), 6.18–6.20 (m, 2H), 5.65 (q_(H-F), 1H,J=7.2 Hz), 3.87 (s, 1H), 3.81 (s, 1H). FABHRMS m/z 303.0497 (M−H⁺,Calc'd 303.0380). Anal. Calc'd for C₁₃H₁₁F₃O₅: C, 51.33; H, 3.64. Found:C, 51.19; H, 3.71.

EXAMPLE 35

Ethyl 6-amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate

Step 1. Preparation of ethyl6-nitro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A mixture of 5-nitrosalicylaldehyde (4.80 g, 28.7 mmol) and ethyl4,4,4-trifluorocrotonate (6.6 g, 39.4 mol) in anhydrous DMF was warmedto 60° C. and treated with anhydrous K₂CO₃ (3.90 g, 28.9 mol). Thesolution was maintained at 60° C. for 20 hours, cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Theorganic extracts were washed with brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo to afford an oil. The oil wasdissolved in diethyl ether (5 mL). Hexanes was added until the solutionbecame cloudy. Upon standing at room temperature overnight the ester wasobtained as yellow crystals (0.856 g, 7% yield). This material was ofsufficient purity to be used in subsequent steps without furtherpurification. ¹H NMR (CDCl₃/300 MHz) 8.15–8.19 (m, 2H), 7.74 (s, 1H),7.09 (d, 1H, J=8.9 Hz), 5.81 (q, 1H, J=5.8 Hz), 4.29–4.39 (m, 2H), 1.35(t, 3H, J=6.0 Hz),

Step 2. Preparation of ethyl6-amino-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

The ester (Step 1) (0.345 g, 1.08 mmol) was stirred in ethanol (10.0 mL)with 10% palladium on charcoal (15 mg) with hydrogen at 1 atmosphere for1 hour. The catalyst was removed by filtration and the solvent removedin vacuo to afford the title compound as an orange-yellow solid (0.298g, 95%): mp 111–115° C. (CD₃OD/300 MHz) 7.69 (s, 1H), 6.69–6.74 (m, 3H),5.65 (q_(H-F), 1H, J=7.2 Hz), 4.26–4.37 (m, 2H), 1.34 (t, 3H, J=7 Hz).FABHRMS m/z 288.0860 (M+H⁺, C₁₃H₁₃F₃NO₃ requires 288.0847). Anal. Calc'dfor C₁₃H₁₂F₃NO₃: C, 54.36; H, 4.21; N, 4.88. Found: C, 54.46; H, 4.27;N, 4.83.

EXAMPLE 36

6-Amino-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Ethyl 6-amino-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example35, Step 2) was hydrolyzed to the carboxylic acid (title compound) by aprocedure similar to that described in Example 1, Step 2: mp 126–133° C.¹H NMR (CD₃OD/300 MHz) 6.81–6.90 (m, 3H), 5.66 (q_(H-F), 1H, J=7.2 Hz).FABHRMS m/z 260.0535 (M+H⁺, C₁₁H₉F₃NO₅ requires 260.0534).

EXAMPLE 37

6-Nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Ethyl 6-nitro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example35, Step 1) was hydrolyzed to the carboxylic acid (title compound) by aprocedure similar to that described in Example 1, Step 2: mp 187–189° C.¹H NMR (CD₃OD/300 MHz) 8.34 (d, 1H, J=2.6 Hz), 8.27 (dd, 1H, J=8.7, 2.6Hz), 7.90 (s, 1H), 7.09 (s, 1H, J=8.7 Hz), 5.81 (q_(H-F), 1H, J=7.2 Hz).EIHRMS m/z 289.0177 (Calc'd 289.0198). Anal. Calc'd for C₁₁H₆F₃NO₅: C,45.69; H, 2.09; N 4.84 Found: C, 45.71; H, 2.08; N 4.75.

EXAMPLE 38

6-Chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-Chloro-2-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 231.9–233.2° C. ¹HNMR (CDCl₃/300 MHz) 7.76 (s, 1H), 7.19 (d, 1H, J=1.8 Hz), 7.09 (d, 1H,J=2.4 Hz), 5.72 (q, 1H, J=6.9 Hz), 2.24 (s, 3H). ¹⁹F NMR (CDCl₃/282 MHz)−79.2 (d, J=6.5 Hz). FABLRMS m/z 299 (M+Li). FABHRMS m/z 293.0196 (M+H,Calc'd 293.0192). Anal. Calc'd for C₁₂H₈ClF₃O₃: C, 49.25; H, 2.76.Found: C, 49.37; H, 2.86.

EXAMPLE 39

8-Chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Chloro-4-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 226.4–227.4° C. ¹HNMR (CDCl₃/300 MHz) 7.79 (s, 1H), 7.23 (d, 1H, J=1.4 Hz), 6.97 (d, 1H,J=1.4 Hz), 5.77 (q, 1H, J=6.8 Hz), 2.29 (s, 3H). ¹⁹F NMR (CDCl₃/282 MHZ)−79.1 (d, J=7.3 Hz). FABLRMS m/z 291 (M−H). EIHRMS m/z 292.0118 (M+,C₁₂H₈ClF₃O₃ Calc'd 292.0114).

EXAMPLE 40

8-Chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Chloro-4-methoxyphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 204.5–206.9° C. ¹HNMR (CDCl₃/300 MHz) 7.78 (s, 1H), 6.98 (d, 1H, J=2.8 Hz), 6.71 (d, 1H,J=2.8 Hz), 5.74 (q, 1H, J=6.9 Hz), 3.79 (s, 3H). FABLRMS m/z 326(M+NH₄). EIHRMS m/z 308.0053 (M+Calc'd 308.0063). Anal. Calc'd forC₁₂H₈ClF₃O₄: C, 46.70; H, 2.61. Found: C, 46.60; H, 2.68.

EXAMPLE 41

6,8-Difluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2,4-Difluorophenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 207–211° C. ¹H NMR (CDCl₃)7.63 (s, 1H), 6.89–6.72 (m, 2H), 5.69 (q, 1H, J=6.7 Hz). Anal. Calc'dfor C₁₁H₅O₃F₅: C, 47.16; H, 1.80. Found: C, 47.28; H, 1.87.

EXAMPLE 42

6-Bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-Bromo-2-chlorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 220.7–221.7° C. ¹HNMR (CDCl₃) 7.58 (s, 1H), 7.44 (d, 1H, J=2.2 Hz), 7.22 (d, 1H, J=2.2Hz), 5.74 (q, 1H, J=6.8 Hz). Anal. Calc'd for C₁₁H₅O₃F₃BrCl: C, 36.96;H, 1.41. Found: C, 37.03; H, 1.44.

EXAMPLE 43

8-Bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Bromo-4-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp>300° C. ¹H NMR(CDCl₃) 7.58 (s, 1H), 7.22 (dd, 1H, J=6.3, 3 Hz), 6.88 (dd, 1H, J=6.1,3.1 Hz), 5.72 (q, 1H, J=6.7 Hz). Anal. Calc'd for C₁₁H₅O₃F₄Br: C, 38.74;H, 1.48. Found: C, 38.82; H, 1.56.

EXAMPLE 44

8-Bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Bromo-4-methylphenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 237–238° C. ¹H NMR(CDCl₃) 7.59 (s, 1H), 7.27 (m, 1H), 6.91 (d, 1H, J=1.4 Hz), 5.69 (q, 1H,J=6.9 Hz), 2.20 (s, 3H). Anal. Calc'd for C₁₂H₈O₃F₃Br: C, 42.76; H,2.39. Found: C, 43.34; H, 2.56.

EXAMPLE 45

8-Bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Bromo-5-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 221.7–223.3° C. ¹HNMR (CDCl₃) 7.81 (s, 1H), 7.38 (dd, 1H, J=7.3, 5.8 Hz), 6.58 (t, 1H,J=8.9 Hz), 5.71 (q, 1H, J=6.7 Hz). Anal. Calc'd for C₁₁H₅O₃F₄Br: C,38.74; H, 1.48. Found: C, 38.70; H, 1.54.

EXAMPLE 46

6-Chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-Chloro-2-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 190.8–193.0° C. ¹HNMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.19 (d of d, 1H, J=2.2 and 9.7 Hz),7.07 (t, 1H, J=1.8 Hz), 5.76 (q, 1H, J=6.7 Hz). FABLRMS m/z 295 (M−H).EIHRMS m/z 295.9876 (M+Calc'd 295.9863). Anal. Calc'd for C₁₁H₅ClF₄O₃:C, 44.54; H, 1.70. Found: C, 44.36; H, 1.85.

EXAMPLE 47

6-Bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-Bromo-2-methoxysalicylaldehyde was converted to the title compound bya procedure similar to that described in Example 1: mp dec. at 244° C.¹H NMR (CD₃OD/300 MHz) 7.71 (s, 1H), 7.18 (d, 1H, J=2.2 Hz), 7.11 (d,1H, J=2.2 Hz), 5.77 (q_(H-F), 1H, J=7.2 Hz), 3.84 (s, 3H). FABLRMS m/z351 (m−H). Anal. Calc'd for C₁₂H₈BrF₃O₅: C, 40.82; H, 2.28. Found: C,40.83; H, 2.30.

EXAMPLE 48

7-(N,N-Diethylamino)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-(N,N-Diethylamino)salicylaldehyde was converted to the title compoundby a procedure similar to that described in Example 1: mp 214.4–215.4°C. ¹H NMR (CD₃OD/300 MHz) 7.67 (s, 1H), 7.06 (d, 1H, J=8.6 Hz), 6.34(dd, 1H, J=8.6, 2.3 Hz), 5.60 (q_(H-F), 1H, J=7.2 Hz), 3.38 (q, 4H,J=7.1 Hz), 1.16 (t, 6H, J=7.1 Hz). ESLRMS m/z 316 (M+H). FABHRMS m/z316.1145 (M+H⁺, Calc'd 316.1161). Anal. Calc'd for C₁₅H₁₆F₃NO₃: C,57.14; H, 5.11; N, 4.44. Found: C, 57.14; H, 5.08; N, 4.44.

EXAMPLE 49

6-[[(Phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

Chlorosulfonic acid (50.0 mL) was cooled to 15° C. and ethyl2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 10, Step 2)(6.21 g, 22.83 mmol) was added. After stirring at −15° C. for 1 hour,the solution was warmed to room temperature and stirred for 16 hours.The solution was added dropwise onto ice (500 mL) with vigorous stirringand extracted with diethyl ether (2×250 mL). The ether layers werecombined, washed with water (2×250 mL), saturated sodium bicarbonate(2×250 mL), and brine (2×250 mL). Hexanes (50 mL) were added and thesolution was dried over sodium sulfate. The solvent was removed in vacuoto afford the ester as a yellow solid (7.41 g, 87%): mp 97.2–98.4° C. ¹HNMR (CDCl₃, 300 MHz) 7.97 (dd, 1H, J=8.6, 2.2. Hz), 7.92 (d, 1H, J=2.2Hz), 7.73 (s, 1H), 7.17 (d, 1H, J=2.2 Hz), 5.82 (q_(H-F), 1H, J=7.2 Hz),4.28–4.39 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 376 (M+Li⁺).

Step 2. Preparation of ethyl6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

The sulfonyl chloride from Step 1 (451.0 mg, 1.22 mmol) and benzylamine(600 mg, 5.62 mmol) were mixed in diethyl ether (25 mL) for 1 hour atroom temperature. The solution was washed with 1N HCl (2×25 mL),saturated sodium bicarbonate (2×25 mL), and brine (2×25 mL). Thesolution was dried over sodium sulfate and dried in vacuo. Theaminosulfonyl was obtained by crystallization from hexanes (431 mg,84%): mp 128.2–131.9° C. ¹H NMR (CDCl₃, 300 MHz) 7.76 (dd, 1H, J=8.4,2.2. Hz), 7.70 (d, 1H, J=2.2 Hz), 7.67 (s, 1H), 7.12–7.30 (m, 5H), 7.05(d, 1H, J=8.4 Hz), 5.78 (q_(H-F), 1H, J=7.2 Hz), 4.68 (m, 2H), 4.19–4.32(m, 2H), 1.37 (t, 3H, J=7.0 Hz). FABLRMS m/z 442 (M+H⁺). FABHRMS m/z442.0936 (M+H⁺, C₂₀H₁₉F₃NO₅S Calc'd 442.0916).

Step 3. Preparation of6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid.

The acid was converted from the ester (step 2) via the method similar tothat described in Example 1, step 2: mp 223.3–224.4° C. ¹H NMR(CD₃OD/300 MHz) 7.31–7.80 (m, 3H), 7.15–7.25 (m, 5H), 7.06 (d, 1H, J=8.3Hz), 5.87 (q_(H-F), 1H, J=7.2 Hz), 4.11 (s, 2H). FABLRMS m/z 420(M+Li⁺). FABHRMS m/z 414.0589 (M+H⁺ Calc'd 414.0623). Anal. Calc'd forC₁₈H₁₄F₃NO₅S: C, 52.30; H, 3.41; N, 3.39. Found: C, 5.16; H, 3.44; N,3.32.

EXAMPLE 50

6-[(Dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 201.2–202.5° C. ¹H NMR (CD₃OD/300 MHz) 7.90 (s, 1H),7.82 (d, 1H, J=2.2 Hz), 7.76 (dd, 1H, J=8.6, 2.2 Hz), 7.19 (d, 1H, J=8.6Hz), 5.91 (q_(H-F), 1H, J=7.2 Hz), 2.70 (s, 6H). FABLRMS m/z 352 (M+H⁺).FABHRMS m/z 352.0466 (M+H+Calc'd 352.0467). Anal. Calc'd forC₁₃H₁₂F₃NO₅S: C, 44.45; H, 3.44; N, 3.99. Found: C, 4.42; H, 3.45; N,3.96.

EXAMPLE 51

6-Aminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 187.9–189.8° C. ¹H NMR (CD₃OD/300 MHz) 7.58–7.88 (m,3H), 7.12 (d, J=8.3 Hz), 5.87 (q_(H-F), 1H, J=7.2 Hz). FABLRMS m/z 324(M+H⁺). FABHRMS m/z 324.0156 (M+H⁺ Calc'd 324.0154). Anal. Calc'd forC₁₁H₈F₃NO₅S*0.74 H₂O: C, 39.26; H, 2.84; N, 4.16. Found: C, 39.33; H,2.82; N, 4.11.

EXAMPLE 52

6-(Methylamino)sulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 207.6–208.6° C. ¹H NMR (CD₃OD/300 MHz) 7.83–7.97 (m,3H), 7.19 (d, 1H, J=8.5 Hz), 5.91 (q_(H-F), 1H, J=7.2 Hz), 3.11 (s, 3H).FABLRMS m/z 338 (M+H⁺). FABHRMS m/z 338.0331 (M+H⁺ Calc'd 338.0310).Anal. Calc'd for C₁₂H₁₁F₃NO₅S: C, 42.73; H, 2.99; N, 4.15. Found: C,42.91; H, 3.06; N, 4.04.

EXAMPLE 53

6-[(4-Morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 215.2–219.3° C. ¹H NMR (CD₃OD/300 MHz) 7.88 (S, 1H),7.81 (d, 1H, J=2.2 Hz), 7.74 (dd, 1H, J=8.6, 2.2 Hz), 5.90 (q_(H-F), 1H,J=7.2 Hz), 3.54–3.70 (m, 4H), 2.94–2.97 (m, 4H). FABLRMS m/z 394 (M+H⁺).FABHRMS 394.0567 (M+H⁺, C₁₅H₁₅F₃NO₆S Calc'd 394.0572).

EXAMPLE 54

6-[(1,1-Dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 229.3–233.5° C. ¹H NMR (CD₃OD/300 MHz) 7.82–7.87 (m,3H), 7.12 (d, 1H, J=8.6 Hz), 5.87 (q_(H-F), 1H, J=7.2 Hz), 1.18 (s, 9H).FABLRMS m/z 380 (M+H⁺). Anal. Calc'd for C₁₅H₁₆F₃NO₅S: C, 47.49; H,4.25; N, 3.69. Found: C, 47.95; H, 4.48; N, 3.55.

EXAMPLE 55

6-[(2-Methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 190.6–192.4° C.: ¹H NMR (CD₃OD/300 MHz) 7.77–7.84 (m,3H), 7.13 (d, 1H, J=8.4 Hz), 5.86 (q_(H-F), 1H, J=7.2 Hz), 2.64 (d, 2H,J=6.8 Hz), 1.66 (sept, 1H, J=6.6 Hz), 0.84 (d, 6H, J=6.6 Hz). FABLRMSm/z 380 (M+H⁺). Anal. Calc'd for C₁₅H₁₆F₃NO₅S: C, 47.49; H, 4.25; N,3.69. Found: C, 47.61; H, 3.34; N, 3.55.

EXAMPLE 56

6-Methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of6-chlorosulfonyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

To chlorosulfonic acid (50.0 mL) chilled to −15° C. was added2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 10) (4.0g, 16.7 mmol). After stirring at −15° C. for 1 hour, the solution waswarmed to room temperature and stirred for 16 hours. The resultingsolution was added dropwise over ice (100 mL) with two diethyl ether(2×75 mL) extractions. The diethyl ether layers were combined, washedwith water (2×75 mL), and brine (2×75 mL, dried over sodium sulfate andconcentrated in vacuo. The resulting solids were triturated withhexane-ethyl acetate (9:1, 100 mL). The6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid wasisolated as a white solid: mp 169–174. ¹H NMR (CD₃OD/300 MHz) 8.18 (d,1H, J=2.7 Hz), 8.06 (dd, 1H, J=8.7, 2.7 Hz), 7.93 (s, 1H), 7.28 (d, 1H,J=8.7 Hz), 6.00 (q, 1H, J=6.6 Hz). EIHRMS m/z 324.9977 (M+, Calcd324.9994).

Step 2. Preparation of6-methylsulfonyl-2-(trifluoromentyl)-2H-1-benzopyran-3-carboxylic acid.

A slurry of the chlorosulfonyl intermediate (Example 49, Step 1) (493mg, 1.44 mmol), sodium bicarbonate (362 mg, 4.32 mmol), and sodiumbisulfite (181 mg, 1.44 mmol) in water (1.5 mL)was heated to 60° C. for1.5 h, followed by the addition of bromoacetic acid (212 mg, 1.55 mmol).The resulting suspension was heated to reflux, followed by the additionof sodium hydroxide solution (50% NaOH soln., 0.10 mL) and water (3.0mL). The solution was reluxed for 8 hours, cooled to room temperature,and acidified to pH 1 with 1N aqueous hydrochloric acid. The solutionwas extracted with ethyl acetate (2×25 mL). The combined ethyl acetatelayers were washed with 1N aqueous hydrochloric acid (2×25 mL), water(2×25 mL), and brine (2×25 mL), dried over sodium sulfate, filtered andconcentrated in vacuo yielding the title compound as an off white solid.(231 mg, 50% yield): mp 208.3–212.4° C. ¹H NMR (CD₃OD, 300 MHz) 7.97 (d,1H, 2.2 Hz), 7.91 (1H, dd, J=8.7, 2.2 Hz), 7.19 (d, 1H, J=8.7 Hz), 5.91(q_(H-F), 1H, J=7.2 Hz), 3.11 (s, 1H) HRLRMS m/z 321 (M−H) FABLRMS m/z321 (M−H). Anal. Calc'd for C₁₂H₉F₃O₅S*0.61 H₂O: C, 43.26; H, 3.09.Found: C, 43.24; H, 3.09.

EXAMPLE 57

8-Chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 167.0–173.8° C. ¹H NMR (CD₃OD/300 MHz) 7.78 (s, 1H),7.72 (d, 1H, J=2.0 Hz), 7.64 (d, 1H, J=2.0 Hz). 7.44 (s, 1H), 7.15–7.23(m, 5H), 6.01 (q_(H-F), 1H, J=7.2 Hz),4.08–4.15 (m, 2H). FABLRMS m/z 454(M+Li⁺). Anal. Calc'd for C₁₆H₁₃ClF₃NO₅S: C, 48.28; H, 2.93; N, 3.13.Found: C, xx; H, xx; N, xx.

EXAMPLE 58

6-N,N-Diethylaminosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 238–240° C. ¹H NMR (CD₃OD/300 MHz) 7.88 (s, 1H), 7.85(d, 1H, J=2.2 Hz), 7.79 (dd, 1H, J=8.5, 2.2 Hz), 7.14 (d, 1H, J=8.5 Hz),5.88 (q_(H—F), 1H, J=7.2 Hz), 3.24 (q, 2H, J=7.3 Hz), 1.11 (t, 3H, J=7.3Hz). FABHRMS m/z 380.0763 (M+H⁺, Calc'd 380.0780). Anal. Calc'd forC₁₅H₁₆F₃NO₄S: C, 47.49; H, 4.25; H, 3.69. Found: C, 47.62; H, 4.30; N,3.72.

EXAMPLE 59

6-Phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

2-Trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 10) (1.32g, 4.85 mmol) was cooled to 0° C. in dichloromethane (50 mL). Aluminumchloride (2.58 g, 19.5 mmol) was added and a dark red solution resulted.A solution of phenylacetyl chloride (1.8 g, 12.1 mmol) indichloromethane (10.0 mL) was added dropwise over 40 minutes. Thesolution was warmed to room temperature and stirred for 16 hours. Thesolution was poured onto ice (200 mL) and extracted with diethyl ether(2×100 mL). The diethyl ether layers were combined, extracted with water(1×100 mL), 1 N HCl (2×100 mL), and saturated sodium bicarbonate (3×100mL). Hexanes (20 mL) were added and the solution was extracted withbrine (1×100 mL). The solution was dried over sodium sulfate and solventwas removed in vacuo. The crude ester was purified by flashchromatography over silica gel (with ethyl acetate as eluant) to affordthe ester that was crystllized from diethyl ether/hexanes (830 mg, 44%):mp 136.2–138.0° C. ¹H NMR (CDCl₃/300 MHz) 7.98 (dd, 2H, J=8.4, 2.0 Hz),7.90 (d, 1H, J=2.0 Hz), 7.29 (s, 1H), 7.22–7.38 (m, 5H), 7.02 (d, 1H,J=8.4 Hz), 5.75 (q_(H-F), 1H, J=7.2 Hz), 4.25–4.40 (m, 2H), 4.21 (s,2H), 1.34 (t, 3H, J=7.0 Hz). FABLRMS m/z 391(M+H⁺).

Step 2. Preparation of6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

The acid was converted from the ester (Step 1) via a method similar tothat described in Example 1, step 2: mp 159.0–164.0° C. ¹H NMR(CD₃OD/300 MHz) 8.04–8.16 (m, 3H), 7.87 (s, 1H), 7.05–7.30 (m, 5H), 5.86(q_(H-F), 1H, J=7.2 Hz), 4.31 (s, 2H). FABLRMS m/z 363 (M+H⁺). Anal.Calc'd for C₁₉H₁₃F₃O₄*0.29 H₂O: C, 62.08; H, 3.73. Found: C, 62.04; H,4.03.

EXAMPLE 60

6-(2,2-Dimethylpropylcarbonyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 59: mp 198–200° C. ¹H NMR (CD₃OD/300 MHz) 7.98–8.06 (m, 2H),7.88 (s, 1H), 7.07 (d, 1H, J=8.9 Hz), 5.86 (q_(H-F), 1H, J=7.2 Hz), 2.88(s, 2H), 1.05 (s, 9H). FABHRMS m/z 343.1175 (M+H⁺, C₁₇H₁₈F₃O₄ requires343.1157). Anal. Calc'd for C₁₇H₁₇F₃O₄: C, 59.65; H, 5.01. Found: C,59.70; H, 4.97.

EXAMPLE 61

6,8-Dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

Step 1: Preparation of ethyl7-methoxy-2-trifluoromethyl-benzopyran-2H-3-carboxylate.

4-Methoxysalicylaldehyde (2.38 g, 15.64 mmol), K₂CO₃ (2.16 g, 15.64mmol) and ethyl 4,4,4-trifluorocrotonate (2.8 mL, 3.16 g, 18.77 mmol)were dissolved in DMF (10 mL). The reaction was stirred at roomtemperature for 24 hours, diluted with water and extracted with Et₂O.The combined Et₂O phases were washed with water, dried over MgSO₄,filtered and concentrated in vacuo yielding an oil. Trituration withhexanes induced crystallization. Collection of the solid by vacuumfiltration yielded the ester as a light brown crystalline solid (1.80 g,38%): mp 78–80° C. ¹H NMR (CDCl₃/300 MHz) δ 7.69 (s. 1H), 7.14 (d, 1H,J=8.1 Hz), 6.59–6.50 (m, 2H), 5.68 (q, 1H, J=7.1 Hz), 4.39–4.24 (m, 2H),3.82 (s, 3H), 1.34 (t, 3H, J=7.3 Hz). FABLRMS m/z 303 (M+H). FABHRMS m/z303.0849 (M+H Calc'd 303.0844). Anal. Calc'd for C₁₄H₁₃F₃O₄: C, 55.63;H, 4.34. Found: C, 55.47; H, 4.31.

Step 2. Preparation of ethyl6,8-dichloro-7-methoxy-2-trifluoromethyl-benzopyran-2H-3-carboxylate.

Chlorine gas (excess) was added to a stirred solution of the ester(Step 1) (1.35 g, 4.47 mmol) in HOAc (30 mL) until the yellow colorpersisted. After 20 minutes, the reaction was sparged with nitrogencausing the reaction to become straw colored. Zinc (0.86 g, 13.40 mmol)was added to this solution with vigorous stirring. After 45 minutes,additional zinc (0.86 g, 13.40 mmol) was added and the reaction wasstirred overnight. The crude mixture was diluted with EtOH and filteredthrough diatomaceous earth. The filtrate was concentrated in vacuoyielding a crystalline mass. This solid was dissolved in EtOAc, washedwith 2N HCl, brine, dried over MgSO₄, filtered and concentrated in vacuoyielding an oil. The oil was dissolved in a minimum of isooctane,inducing crystallization. Vacuum filtration of the suspension yieldedtan needles (1.078 g) which were recrystallized from isooctane yieldingthe dichloro ester as tan crystals (0.71 g, 43%) of suitable purity touse in the next step: mp 113.3–115.1° C. ¹H NMR (acetone-d₆/300 MHz)7.88 (s, 1H), 7.63 (s, 1H), 6.02 (q, 1H, J=6.8 Hz), 4.38–4.22 (m, 2H),3.93 (s, 3H), 1.31 (t, 3H, J=7.1 Hz). ¹⁹F NMR (acetone-d₆/282 MHz)−80.00 (d, J=7.2 Hz).

Step 3: Preparation of6,8-dichloro-7-methoxy-2-trifluoromethyl-benzopyran-2H-3-carboxylicacid.

To a stirred solution of the dichloro ester from Step 2 (0.686 g, 1.848mmol) in THF (10 mL) and EtOH (3 mL) was added NaOH (0.81 mL of 2.5 Maqueous solution, 2.03 mmol) in one portion. After stirring overnightthe reaction was partially concentrated, diluted with H₂O and washedwith diethyl ether. The resulting aqueous phase was sparged withnitrogen and acidified with 2N HCl solution causing the solution tobecome turbid. Filtration of this suspension yielded the title compoundas a white powder (0.559 g, 88%): mp 195.6–199.1° C. ¹H NMR (CDCl₃/300MHz) 7.90 (s, 1H), 7.64 (s, 1H), 6.01 (q, 1H, J=6.8 Hz), 3.94 (s, 3H).¹⁹F NMR (CDCl₃/282 MHz) −79.63 (d, J=7.1 Hz). FABLRMS m/z 349 (M+Li).EIHRMS m/z 341.9681 (M+, Calc'd 341.9673). Anal. Calc'd forC₁₂H₇Cl₂F₃O₄: C, 42.01; H, 2.06. Found: C, 41.76; H, 2.14.

EXAMPLE 62

2-Trifluoromethyl-2H-naphtho[1,2-b]pyran-3-carboxylic acid

Step 1. Preparation of ethyl2-trifluoromethyl-3H-naphthopyran-carboxylate.

A mixture of 2-hydroxy-1-naphthaldehyde (8.6 g, 0.050 mol) and ethyl4,4,4-trifluorocrotonate (9.2 g, 0.055 mol) dissolved in anhydrousdimethylformamide (DMF) and treated with anhydrous K₂CO₃ (13.8 g, 0.100mol). The solution was maintained at room temperature for 50 hours anddiluted with water. The solution was extracted with ethyl acetate, andthe combined extracts were washed with brine, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to afford 4.8 g of an oil. Theoil was purified by HPLC, eluting with hexanes:ethyl acetate (30:1). Theappropriate fractions were concentrated to afford 1.6 g (10%) of thenapthopyran ester as a yellow solid.

Step 2. Preparation of 2-trifluoromethyl-3H-naphthopyran-carboxylicacid.

A solution of the ester from Step 1 (0.8 g, 2.5 mmol) was dissolved in40 mL of ethanol and 10 mL of tetrahydrofuran, treated with sodiumhydroxide (2.5 N, 10 mL, 25 mmol) and stirred at room temperature for 16hours. The reaction mixture was acidified with 1.0 N HCl, whereupon asolid formed that was isolated by filtration. The solid was washed with20 mL of water to afford 0.7 g (95%) of the title compound as a yellowsolid: mp 245.9–248.6° C. ¹H NMR (acetone-d₆/300 MHz) 8.57 (s, 1H), 8.28(d, 1H, J=8.7 Hz), 8.03 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.7), 7.67 (m,1H), 7.50 (m, 1H), 7.28 (d, 1H, J=9.0), 5.96 (q_(H-F), 1H, J=7.2 Hz).FABHRMS m/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd forC₁₅H₉O₃F₃+3.31% H₂O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.

EXAMPLE 63

2-Trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid

2-Hydroxy-napth-1-aldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 244.7–249.8° C. ¹HNMR (CDCl₃/300 MHz) 8.61 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.90 (d, 1H,J=8.9 Hz), 7.82 (d, 1H, J=8.3 Hz), 7.63 (t, 1H, J=8.1 Hz), 7.47 (t, 1H,J=8.1 Hz), 7.23 (d, 1H, J=9.1 Hz), 5.84 (q, 1H, J=6.8 Hz). ¹⁹F NMR(CDCl₃/282 MHz) −79.56 (d, J=7.3 Hz). FABLRMS m/z 295 (M+H). FABHRMS m/z295.0560 (M+H, Calc'd 295.0582). Anal. Calc'd for C₁₅H₉F₃O₃: C, 61.23;H, 3.08. Found: C, 60.85; H, 3.12.

EXAMPLE 64

2-Trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid

3-Hydroxynapthalene-2-carboxylic acid was converted to3-hydroxynapthalene-2-carboxaldehyde by a similar procedure to thatdescribed in Example 24, Steps 1 & 2. The3-hydroxynapthalene-2-carboxaldehyde was converted to the title compoundby a procedure similar to that described in Example 1: mpdecompose >300° C. ¹H NMR (CD₃OD/300 MHz) 7.99 (s, 1H), 7.90 (s, 1H),7.84 (d, 1H, J=8.2 Hz), 7.74 (d, 1H, J=8.2 Hz), 7.50 (t, 1H, J=8.2 Hz),7.39 (t, 1H, J=8.2 Hz), 7.34 (s, 1H), 5.77 (q, 1H, J=6.6 Hz). EIHRMS m/z294.0474 (M+, Calc'd 294.0504).

EXAMPLE 65

6-Chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid

Step 1: Synthesis of 5-chloro-thiosalicylaldehyde.

Tetramethylethylenediamine (TMEDA) (10.44 mL, 8.035 g, 69.15 mmol) wasadded via syringe to n-BuLi (43.22 mL of 1.6 M in hexanes, 69.15 mmol)and the solution was chilled to 0° C. A solution of 4-chlorothiophenol(5.00 g, 34.57 mmol) in cyclohexane (25 mL) was added with stirring over1 hour. The resulting tan slurry was stirred overnight at roomtemperature, chilled to 0° C., and DMF (2.94 mL, 2.78 g, 38.03 mmol) wasadded via syringe over 2 minutes. The resulting gummy slurry was stirredat room temperature for 30 hours and became a powdery suspension. Amixture of 2 N HCl and ice was added to the reaction mixture until thepH became acidic (pH=1). During this addition, the mixture warmed andbecame first red and then pale yellow. This mixture was extracted withethyl acetate. The combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated in vacuo yielding a clearred-brown oil. This oil was triturated with hexanes yielding a red-brownsemisolid. This semisolid was purified by plug flash chromatography oversilica gel, eluting with 1:1, hexanes:dichloromethane to afford5-chloro-thiosalicylaldehyde (0.858 g, 14%) as an intensely yellow solidsuitable for use without further purification.

Step 2: Preparation of ethyl6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2-H-3-carboxylate.

5-Chloro-thiosalicylaldehyde (Step 1) (0.84 g, 4.86 mmol) was added toDMF (3 mL) and ethyl 4,4,4-trifluorocrotonate (1.10 mL, 1.22 g). Withstirring, K₂CO₃ (0.67 g, 4.86 mmol) was added causing the reaction tobecome a deep red. After stirring overnight at room temperature, thereaction was diluted with diethyl ether and washed with water, saturatedNaHCO₃ solution, aqueous KHSO₄ solution (0.25 M), brine, dried overMgSO₄, filtered and concentrated in vacuo yielding an oil. The oil waspurified by flash chromatography (5:1; hexanes: ethyl acetate) yieldingupon concentration ethyl6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2-H-3-carboxylate as abright orange solid (0.492 g, 31%): mp 94.6–97.4° C. ¹H NMR (acetoned₆/300 MHz) δ 8.01 (s, 1H), 7.71 (d, 1H, J=2.2 Hz), 7.50 (d, 1H, J=8.5Hz), 7.44 (d of d, 1H, J=2.3, 8.3 Hz), 5.07 (q, 1H, J=8.5 Hz), 4.42–4.23(m, 2H), 1.35 (t, 3H, J=7.1 Hz). FABLRMS m/z 329 (M+Li).

Step 3: Preparation of6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2-H-3-carboxylic acid.

To a stirred solution of the ester from Step 2 (0.413 g, 1.280 mmol) inTHF:EtOH:H₂O (7:2:1, 10 mL) was added NaOH solution (0.56 mL of 2.5 Nsolution, 1.408 mmol) with stirring. After stirring overnight, thereaction was partially concentrated in vacuo to remove the organicsolvents, diluted with H₂O and washed with several portions of diethylether. Acidification of the stirred aqueous phase with concentrated HClcaused precipitation of a flocculent yellow precipitate. Vacuumfiltration of the suspension yielded6-chloro-2-trifluoromethyl-benzo-1-thiopyran-2H-3-carboxylic acid as ayellow powder (0.25 g, 66%): mp 188.8–198.7° C. ¹H NMR (acetone d₆/300MHz) δ 8.02 (s, 1H), 7.71 (d, 1H, J=2.22 Hz), 7.50 (d, 1H, J=8.5 Hz),7.44 (d of d, 1H, J=2.2, 8.5 Hz), 5.05 (q, 1H, J=8.6 Hz). ¹⁹F NMR(Acetone d₆/282 MHz) d −75.22 (d, J=8.7 Hz). FABLRMS m/z 301 (M+Li);ESLRMS (neg. ion) m/z 293 (M−H).

EXAMPLE 66

(S)-6-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

To a solution of 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid (Example 1, Step 2)(12.00 g, 43.07 mmol) and (S)(−)-α-methylbenzylamine (2.61 g, 21.54 mmol) in methyl-tert-butyl ether(30 mL) was slowly added n-heptane (200 mL) until the mixture becamecloudy. The mixture was heated (steam bath) to boiling and set aside for24 h during which time crystals formed. Filtration of the suspensionyielded a crystalline product (5.5 g) which was recrystallized frommethyl-tert-butyl ether (30 mL) and n-heptane (200 mL) yielding uponfiltration a white solid (3.1 g). This solid was dissolved in EtOAc (100mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2×50 mL),dried over MgSO₄ and concentrated in vacuo yielding a white solid.Recrystallization of this solid from methyl-t-butyl ether/n-heptaneyielded the title compound as the highly enriched isomer, a white solid(2.7 g, 45%): mp 126.7–128.9° C. ¹H NMR (CDCl₃/300 MHz) 7.78 (s, 1H),7.3–7.1 (m, 3H), 6.94 (d, 1H, J=8.7 Hz), 5.66 (q, 1H, J=6.9 Hz). Anal.Calc'd for C₁₁H₆O₃F₃Cl: C, 47.42; H, 2.17; N, 0.0. Found: C, 47.53; H,2.14; N, 0.0. This compound was determined to have an optical purity ofgreater than 90% ee.

Procedure for Determining Optical Purity.

To a solution of the free acid (title compound) (0.005 g, 0.017 mmol) inethyl acetate (1.5 mL) in a test tube was added(trimethylsilyl)diazomethane (30 μL of 2.0 N solution in hexanes, 60mmol). The resulting yellow solution was warmed until the solution beganto gently boil and then was allowed to cool to room temperature andstand for 0.08 hours. With vigorous mixing, the solution was quenchedwith aqueous 1 N HCl (1.5 mL). The layers were separated and a sample ofthe ethyl acetate fraction (0.3 mL) was transferred to a vial,concentrated under a stream of nitrogen, was diluted with hexane (totalof 1 mL) and a sample (10 μL) analyzed by chiral chromatography. TheHPLC utilized a Daicel ChiralPak AD column eluting with 10%isopropanol-hexane at 0.5 mL/min using a UV detector set at 254 nM.

EXAMPLE 67

(S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

To a solution of6-trifluoromethoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid(Example 16)(17.72 g, 54.00 mmol) and (−)-cinchonidine (7.95 g, 27.04mmol) in methyl-tert-butyl ether (100 mL) heated on a steam-bath wasadded n-heptane (200 mL). The mixture was heated on the steam bath toboiling and allowed to cool for 4 h during which time crystals formed.Filtration of the suspension yielded a crystalline solid (18.7 g). Thissolid was dissolved in 2-butanone (30 mL) followed by the addition ofn-heptane (500 mL). After standing for 16 hours, the resultingsuspension was filtered yielded a white solid (10.3 g). This solid wasdissolved in ethyl acetate (150 mL), washed with 1 N hydrochloric acid(100 mL) and brine (2×50 mL), dried over MgSO₄, filtered, andconcentrated in vacuo yielding a viscous yellow oil (5.2 g, 59%): ¹H NMR(acetone-d₆/300 MHz) 7.16 (s, 1H), 6.77 (d, 1H, J=2.7 Hz), 6.94 (d, 1H,J=8.7 Hz), 6.64 (m, 1H), 6.39 (d, 1H, J=8.7 Hz) 5.13 (q, 1H, J=7.2 Hz).Anal. Calc'd for C₁₂H₆O₄F₆: C, 43.92; H, 1.84; N, 0.0. Found: C, 43.79;H, 1.83; N, 0.0. This compound was determined to have an optical purityof greater than 90% ee. Chiral purity was determined as describe inExample 66.

EXAMPLE 68

(S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

To a solution of6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid (Example 8)(11.4 g, 34.1 mmol) and(S)-(−)-2-amino-3-phenyl-1-propanol (2.57 g, 17.00 mmol) was addedn-heptane (200 mL) and the mixture set aside for 16 h. The resultingsuspension was filtered yielding a solid (3.8 g). This solid wasrecrystallized from 2-butanone (20 mL) and n-heptane (200 mL) yieldingupon filtration a white solid (3.0 g). This solid was dissolved in ethylacetate (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine(2×50 mL), dried over MgSO₄ and concentrated in vacuo yielding a whitesolid. This solid was recrystallized from n-heptane yielding the titlecompound of high optical purity as a crystalline solid(1.7 g, 30%): mp175.4–176.9° C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H),7.12 (s, 1H), 5.83 (q, 1H, J=7.1 Hz), 1.48 (s, 9H). Anal. Calc'd forC₁₅H₁₄O₃F₃Cl: C, 53.83; H, 4.22; N, 0.0; Cl, 10.59. Found: C, 53.78; H,4.20; N, 0.0; Cl, 10.65. This compound was determined to have an opticalpurity of greater than 90% ee. Chiral purity was determined as describein Example 66.

EXAMPLE 69

6-[[(2-Furanylmethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The title compound was prepared by a similar procedure to that describedin Example 49: mp 170–173° C. ¹H NMR (CD₃OD/300 MHz) 7.78 (s, 1H),7.66–7.76 (m, 2H), 7.18–7.22 (m, 1H), 7.00–7.08 (m, 1H), 6.12–6.18 (m,1H), 6.02–6.06 (m, 1H), 5.85 (q, 1H, J=7.0 Hz), 4.13 (s, 2H). EIHRMS m/z403.0332 (M+, Calc'd 403.0337).

EXAMPLE 70

6-[(Phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared analogous to theprocedure described in Example 56: mp 172–176° C. ¹H NMR (CD₃OD/300MHz)7.73 (s, 1H), 7.43–7.56 (m, 2H), 7.21–7.33 (m, 3H), 7.20–7.21 (m,3H), 5.88 (q, 1H, J=7.0 Hz), 4.83 (s, 2H). EIHRMS m/z 398.0399 (M+,Calc'd 398.0436).

EXAMPLE 71

6-[[(Phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared analogous to theprocedure described in Example 49: mp 187–190° C. ¹H NMR (CD₃OD/300 MHz)7.82 (s, 1H), 7.74–7.90 (m, 2H), 7.08–7.29 (m, 6H), 5.89 (q, 1H, J=6.8),3.12 (t, 2H, J=7.3 Hz), 2.72 (t, J=7.3 Hz). EIHRMS m/z 427.0675 (M+,Calc'd 427.0701)

EXAMPLE 72

7-Chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-Chlorosalicylic acid was converted to 3-chlorosalicylaldehyde by aprocedure similar to that described in Example 24, Steps 1 & 2. The3-chlorosalicylaldehyde was converted to the title compound by aprocedure similar to Example 1: mp 175.2–177.6° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.51 (d, 1H, J=7.8 Hz), 7.12 (m, 2H),5.86 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 285.0114 (M+Li, Calc'd285.0118). Anal. Calc'd for C₁₁H₆ClF₃O₃: C, 47.42; H, 2.17; Cl, 12.72.Found: C, 47.54; H, 2.37; Cl, 12.85.

EXAMPLE 73

6-Chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of 3-iodo-5-chlorosalicylaldehyde

N-Iodosuccinimide (144.0 g, 0.641 mole) was added to a solution of5-chlorosalicyaldehyde (100 g, 0.638 mole) in dimethylformamide (400mL). The reaction mixture was stirred for two days at room temperature.Additional N-iodosuccinimide (20 g, 0.089 mole) was added and thestirring was continued for an additional two days. The reaction mixturewas diluted with ethyl acetate (1 liter), washed with hydrochloric acid(300 mL, 0.1 N), water (300 mL), sodium thiosulfate (300 mL, 5%), andbrine (300 mL) It was dried over MgSO₄, and was concentrated to drynessto afford the desired aldehyde as a pale yellow solid (162 g; 90%): mp84.8–86.7° C. ¹H NMR (CDCl₃/300 MHz) 11.67 (s. 1H), 9.71 (s, 1H), 7.92(d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=2.6 Hz). FABLRMS m/z 281.0 (M−H).ESHRMS m/z 280.8851 (M−H, Calc'd. 280.88630).

Step 2. Preparation of ethyl6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate

5-Chloro-3-iodosalicylaldehyde (20 g, 70.8 mmol), ethyl4,4,4-trifluorocrotonate (17.85 g, 106 mmol), and triethylamine (14.33g, 142 mmol) were dissolved in DMSO (200 mL). The reaction mixture wasstirred at 90° C. for three days. The reaction mixture was poured intoethyl acetate (800 mL). It was extracted with 10% HCl (2×200 mL),saturated aqueous NaHCO₃ (2×200 mL), and water (2×200 mL). The ethylacetate phase was dried over MgSO₄, filtered and evaporated to yield abrown solid. It was then run through a plug of silica with ethylacetate-hexane (1:20). The solvent was evaporated to give a yellowsolid, that was recrystallized in hexane to afford the ester as a whitesolid (19.61 g, 64%): mp 92.1–93.9° C. ¹H NMR (CDCl₃/300 MHz) 7.71 (d,1H, J=2.2 Hz), 7.56 (s, 1H), 7.20 (d, 1H, J=2.2 Hz), 5.81 (q, 1H, J=6.7Hz), 4.37–4.29 (m, 2H), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 431.9 (M−H).EIHRMS m/z 431.9269 (M−H, Calc'd. 431.9237).

Step 3. Preparation of6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

The ester (Step 2) was converted to the acid by a procedure similar tothe method described in Example 1, Step 2: mp 220–223° C. ¹H NMR(CD₃OD/300 MHz) 7.77 (d, 1H, J=2.2 Hz), 7.71 (s, 1H), 7.41 (d, 1H, J=2.2Hz), 5.87 (q, 1H, J=7.0 Hz). EIHRMS m/z 403.8893 (M−H, Calc'd.403.8924). Anal. Calc'd for C₁₁H₅ClF₃IO₃: C, 32.66; H, 1.25. Found: C,33.13; H, 1.29.

EXAMPLE 74

8-Bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate

A mixture of 3-bromo-5-chlorosalicylaldehyde (1.9 g, 4.2 mmol),potassium carbonate (0.58 g, 4.2 mmol), and ethyl4,4,4-trifluorocrotonate (0.79 g, 4.7 mmol) was stirred inN,N-dimethylformamide (5 mL) at 95° C. for 18 h. Water (100 mL) wasadded and the mixture was extracted with ether (3×50 mL). The combinedorganic extracts were washed with sodium hydroxide (10 mL) and water(2×50 mL). After drying over MgSO₄ and concentrating, the mixturefiltered through of a pad of silica eluting with ethyl acetate-hexanes(1:4). The eluant was concentrated and a light yellow solid wascrystallized from cold hexane (0.43 g, 26%): mp 101.0–102.2° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.65 (d, H, J=2.4 Hz), 7.61 (d, H,J=2.4 Hz), 6.03 (q_(H-F), 1H, J=6.9 Hz), 4.34 (m, 2H), 1.33 (t, 3H,J=7.5 Hz). ESHRMS m/z 384.9435 (M−H, Calc'd 384.9454). Anal. Calc'd forC₁₃H₉BrClF₃O₃: C, 40.50; H, 2.35. Found: C, 40.61; H, 2.40.

Step 2. Preparation of8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Ethyl 8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-caboxylate(0.3 g), ethanol (15 mL), tetrahydrofuran (10 mL), and sodium hydroxidesolution (10 mL, 2.5 N) were stirred at room temperature for 16 h.Hydrochloric acid (1 N) was added until the mixture was acidic to pHpaper. The addition of water (50 mL) caused the formation of aprecipitate which was collected by filtration yielding the titlecompound as a white solid (0.2 g, 72%): mp 227.8–228.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H, J=2.4 and J=28.8 Hz),6.00 (q_(H-F), 1H, J=7.2 Hz). FABHRMS m/z 356.9134 (M+H, Calc'd356.9141). Anal. Calc'd for C₁₁H₅BrClF₃O₃: C, 36.96; H, 1.41. Found: C,37.05; H, 1.33.

EXAMPLE 75

6-Formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A 50 mL round bottom flask was charged with 5-formylsalicylaldehyde(3.21 g, 21.39 mmol), ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g,23.53 mmol), dimethylformamide (15 mL) and potassium carbonate (2.95 g,21.39 mmol) and heated to 60° C. for 12 hours. Additional ethyl4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol) was added and thereaction heated for 16 hours at 75° C. After cooling to roomtemperature, the reaction was partitioned between H₂O and diethyl ether.The organic phase was washed with saturated NaHCO₃ solution, KHSO₄solution (0.25 M), brine, treated with decolorizing carbon (warmedgently). The resulting black suspension was dried over MgSO₄, vacuumfiltered through diatomaceous earth, and concentrated in vacuo yieldingan orange crystalline mass. This material was recrystallized from hothexanes yielding the ester (1.51 g, 24%) as orange crystals: mp84.3–86.2° C. ¹H NMR (acetone-d₆/300 MHz) 9.96 (s, 1H), 8.06 (d, 1H, J=2Hz), 8.02 (s, 1H), 7.99 (dd, 1H, J=8.5, 2.0 Hz), 7.24 (d, 1H, J=8.5 Hz),5.99 (q, 1H, J=7.1 Hz), 4.43–4.25 (m, 2H), 1.34 (t, 3H, J=7.3 Hz).FABLRMS m/z 301 (M+H). EIHRMS m/z 300.0605 (M+, Calc'd 300.0609). Anal.Calc'd for C₁₄H₁₁F₃O₄: C, 56.01; H, 3.69. Found: C, 56.11; H, 3.73.

Step 2. Preparation of6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

The ester (Step 1) was converted to the acid via a method similar tothat described in Example 1, Step 2: mp 211.3–215.7° C. ¹H NMR(acetone-d₆/300 MHz) 9.97 (s, 1H), 8.07 (d, 1H, J=2.0 Hz), 8.03 (s, 1H),8.00 (dd, 1H, J=8.3, 2.0 Hz), 7.25 (d, 1H, J=8.5 Hz), 5.98 (q, 1H, J=6.9Hz). FABLRMS m/z 273 (M+H). EIHRMS m/z 272.0266 (M+, Calc'd 272.0296).Anal. Calc'd for C₁₂H₇F₃O₄: C, 52.95; H, 2.59. Found: C, 52.62; H, 2.58.

EXAMPLE 76

6-Chloro-8-Formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of 4-chloro-2,6-bis(hydroxymethyl)phenol.

Potassium hydroxide (84.82 g, 1.30 mole) was dissolved in H₂O (200 mL)in a two liter 3-neck round bottom flask fitted with thermocouple,mechanical stirrer, and stopper. With stirring, 4-chlorophenol (128.56g, 1.0 mole) was added with cooling (ice bath) resulting in thetemperature rising to 26° C. Formalin (230 mL of 37% aqueous solution,2.83 mole) was added portion-wise maintaining the temperature below 25°C. The reaction was warmed to 35° C. for 48 hours. To this solution wasadded aqueous acetic acid (80.0 mL, 84.1 g, 1.40 mole in 800 mL H₂O)causing the solution to become turbid. Vacuum filtration of thesuspension yielded a tan solid. The solid was stirred with acetone (100mL) and the insoluble product collected by vacuum filtration. Thesolution was diluted with hexanes yielding several crops of the diol asfine tan needles (35.0 g, 19%). mp 160.6–163.3° C. ¹H NMR (acetone-d₆,NaOD, D₂O/300 MHz) 6.69 (s, 2H), 4.48 (s, 4H), 7.88 (d, 1H, J=2.6 Hz),7.75 (d, 1H, J=2.6 Hz), 6.08 (q, 1H, J=6.9 Hz). ESLRMS m/z 206 (M+NH₄⁺). ESHRMS m/z 187.0131 (M−H, Calc'd 187.0162).

Step 2. Preparation of 5-chloro-3-formyl-salicylaldehyde.

To a stirred suspension of diol (Step 1) (33.0 g, 0.18 mole) inchloroform (1.5 L) in a 2 L round bottom flask was added manganesedioxide (139 g, 1.60 mole) and the resulting suspension heated to agentle reflux for 10 hours. The reaction was allowed to cool to roomtemperature, was filtered through diatomaceous earth, concentrated invacuo, presorbed on silica gel and purified by flash chromatography(hexane/ethyl acetate) yielding the as a mustard colored powderdialdehyde (22.42 g, 67%): mp 120.7–122.8° C. This, solid was ofsuitable purity to use in the next step without further purification.

Step 3. Preparation of ethyl6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A stirred solution of the dialdehyde (Step 2)(1.13 g, 6.14 mmol),dimethyl sulfoxide (6 mL), ethyl 4,4,4-trifluorocrotonate (1.37 mL, 1.55g, 9.21 mmoL) and triethylamine (1.71 mL, 1.24 g, 12.28 mmol) in a roundbottom flask fitted with condenser was heated to 80° C. for 8 h. Uponcooling to room temperature the reaction was diluted with diethyl ether(100 mL) and the resulting mixture washed with aqueous sodiumbicarbonate solution (3×75 mL), 1 N HCl solution (3×70 mL), and brine(1×75 mL), dried over MgSO₄, filtered and concentrated in vacuo yieldinga tan powder. This powder was taken up in hot hexane-ethyl acetate andfiltered to remove insoluble matter. Upon cooling of the filtrate,crystallization followed by vacuum filtration yielded the desired esteras tan crystals (0.726 g, 35%): mp 118.1–119.7° C. This material was ofsuitable purity to use without further purification.

Step 4. Preparation of6-chloro-8-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

To a stirred solution of the ester (Step 3)(0.284 g, 0.849 mmol) inTHF:EtOH:H₂O (7:2:1, 5 mL) was added aqueous NaOH solution (0.41 mL of2.5 M, 1.02 mmol). After stirring 40 hours, the reaction was partiallyconcentrated in vacuo to remove the organic solvents, diluted with H₂O,washed with diethyl ether, sparged with nitrogen to remove trace diethylether, and acidified with concentrated HCl yielding a suspension. Vacuumfiltration of the suspension yielded the title compound as a pale yellowpowder (0.160 g, 23%). mp 243.3–252.4° C. ¹H NMR (acetone-d₆/300 MHz)10.39 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H, J=2.6 Hz), 7.75 (d, 1H, J=2.6Hz), 6.08 (q, 1H, J=6.9 Hz). FABLRMS m/z 307 (M+H). ESHRMS m/z 304.9839(M−H, Calc'd 304.9828). Anal. Calc'd for C₁₂H₆Cl₁F₃O₄: C, 47.01; H,1.97. Found: C, 46.64; H, 1.86.

EXAMPLE 77

6-Bromo-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

7-(1,1-Dimethylethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid (Example 12)(0.6 g, 2 mmol), chloroform (50 mL), iron filings (0.01g, 0.2 mmol), and bromine (0.48 g, 3.00 mmol) were stirred at reflux for16 h. The mixture was allowed to cool and was washed with brine (2×50mL). After drying over MgSO₄, the mixture was filtered, concentrated invacuo, and the residue crystallized from ether-hexanes yielding thetitle compound as a white solid (0.5 g, 66%): mp 198.6–199.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.85 (s, 1H), 7.72 (s, 1H), 7.13 (s, 1H), 5.83 (q,1H, J=7.2 Hz), 1.5 (s, 9H). Anal. Calc'd for C₁₅H₁₄O₃F₃Br: C, 47.52; H,3.72; N, 21.07. Found: C, 47.42; H, 3.68; N, 21.15.

EXAMPLE 78

5,6-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

5,6-Dichlorosalicylaldehyde was prepared by the procedure described inCragoe, E. J.; Schultz, E. M., U.S. Pat. No. 3,794,734, 1974. Thissalicylaldehyde was converted to the title compound by a similarprocedure to that described in Example 1: mp 211.5–213.5° C. ¹H NMR(acetone-d₆/300 MHz) 8.09 (s, 1H), 7.63 (d, 1H, J=8.9 Hz), 7.12 (d, 1H,J=8.9 Hz), 5.94 (q, 1H, J=7.0 Hz). ESLRMS m/z 311 (M−H). EIHRMS m/z311.9583 (M+, Calc'd 311.9568). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C, 42.20;H, 1.61. Found: C, 42.33; H, 1.67.

EXAMPLE 79

6-Cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A 50 mL round bottom flask was charged with hydroxylamine HCl (0.255 g,3.67 mmol), ethyl6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 75,Step 1) (1.00 g, 3.34 mmol), sodium acetate (0.301 g, 3.67 mmol),ethanol (10 mL), and H₂O (2 mL). The reaction was stirred at roomtemperature for 18 hours, then diluted with H₂O and diethyl ether. Thelayers were separated and the organic phase washed with H₂O, brine,dried over MgSO₄, filtered, and concentrated in vacuo yielding an orangesemi-crystalline mass. Recrystallization of this solid from hot ethylacetate and isooctane yielded the oxime (0.578 g, 55%): mp 113.0–116.2°C. ¹H NMR (acetone-d₆/300 MHz) 10.46 (s, ca. 1 exch.), 8.11 (s, 2H),7.92 (s, 1H), 7.72 (d, 1H, J=2 Hz)), 7.68 (dd, 1H, J=8.5, 2.0 Hz), 7.07(d, 1H, J=8.5 Hz), 5.89 (q, 1H, J=7.1 Hz), 4.43–4.22 (m, 2H), 1.34 9t,3H, J=7.3 Hz). FABLRMS m/z 316 (M+H). EIHRMS m/z 315.0719 (M+, Calc'd315.0733). Anal. Calc'd for C₁₄H₁₂F₃N₁O₄: C, 53.34; H, 3.84; N 4.44.Found: C, 53.85; H, 3.90; N, 4.19.

Step 2. Preparation of ethyl6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

To a stirred solution of oxime (Step 1) (0.264 g, 0.840 mmol) in dioxane(4.5 mL) in a 25 mL pear-shaped flask was added trifluoroaceticanhydride (0.130 mL, 0.194 g, 0.924 mmol) and triethylamine (0.140 mL,0.102 g, 1.008 mmol). The reaction was stirred at room temperature for12 hours, then heated to 85° C. for 4 hours. After cooling to roomtemperature, aqueous HCl (50 ml, 1 N HCL) was added, and the resultingmixture extracted with ethyl acetate. The ethyl acetate phase was washedwith chilled aqueous HCl (1 N), brine, dried over Na₂SO₄, filtered,concentrated in vacuo yielding a pale yellow oil. This oil wasresubmitted to similar reaction conditions. After dissolution of thepale yellow oil in dioxane (4.5 mL), trifluoroacetic anhydride (0.130mL, 0.194 g, 0.924 mmol) and triethylamine (0.140 mL, 0.102 g, 1.008mmol) were then added. After stirring 3 hours at room temperature, moretriethylamine 0.50 mL, 0.36 g, 3.6 mmol) was added and then heated to85° C. for 3 hours. After cooling to room temperature, aqueous HCl (50ml, 1 N HCL) was added, and the resulting mixture extracted with ethylacetate. The ethyl acetate phase was washed with chilled aqueous HCl (1N), brine, dried over Na₂SO₄, filtered, concentrated in vacuo yielding apale yellow oil. Addition of hexanes induced crystallization followed byvacuum filtration yielded the title compound (0.101 g, 40%) as a yellowpowder: mp 101.6–106.1° C. ¹H NMR (acetone-d₆/300 MHz) 7.97 (d, 1H,J=2.2 Hz), 7.95 (s, 1H), 7.82 (dd, 1H, J=8.5, 2.0 Hz), 7.24 (d, 1H,J=8.5 Hz), 6.01 (q, 1H, J=7.1 Hz), 4.38–4.24 (m, 2H), 1.34 (t, 3H, J=7.3Hz). FABLRMS m/z 298 (M+H). EIHRMS m/z 297.0575 (M+, Calc'd 297.0613).

Step 3. Preparation of6-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

To a stirred solution of the ester (Step 2)(0.077 g, 0.259 mmol) inTHF-EtOH—H₂O (7:2:1, 2 mL) in a 5 mL pear-shaped flask was added aqueousNaOH (0.13 mL, 2.5 N solution) in one portion. After stirring for 6hours at room temperature the solution was partially concentrated invacuo to remove most of the THF and EtOH. The resulting solution wasdiluted with H₂O and washed with diethyl ether. The resulting aqueousphase was sparged with nitrogen to remove trace diethyl ether and wasacidified with concentrated HCl yielding a sticky suspension. Thesuspension was extracted with diethyl ether and the ether was dried overMgSO₄, filtered and concentrated in vacuo yielding a pale yellow oil.This oil was crystallized from methylene chloride-hexanes yielding thetitle compound (0.041 g, 59%) as a tan powder: mp 185.1–186.1° C. ¹H NMR(acetone-d₆/300 MHz) 7.99–7.94 (m, 2H), 7.83 (dd, 1H, J=8.5, 2.0 Hz),7.25 (d, 1H, J=8.5 Hz), 5.99 (q, 1H, J=7.0 Hz). FABLRMS m/z 270 (M+H).EIHRMS m/z 269.0316 (M+, Calc'd 269.0300).

EXAMPLE 80

6-Hydroxymethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

To a chilled (ice bath), stirred solution of6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example75, Step 2) (0.133 g, 0.489 mmol) in THF (1 mL) and ethanol (1 mL) in a10 mL round bottom flask was added NaBH₄ (0.020 g, 0.528 mmol) in twoportions. The reaction was allowed to warm to room temperature and moreNaBH₄ (0.050 g, 1.322 mmol) was added. The total reaction time was 3hours. The reaction was quenched with aqueous HCl (1 N solution) and wasextracted with chloroform. The organic phase was dried over MgSO₄,filtered and concentrated in vacuo yielding a foam. This crude productwas purified by flash chromatography (silica gel 60, eluant 1:1,hexane-ethyl Acetate with 2% acetic acid). The product collected fromthe chromatography was recrystallized from hexanes and ethyl acetate,and collected by vacuum filtration yielding the title compound (0.042 g,31%) as a very pale yellow powder: mp 177.5–180.8° C. ¹H NMR(acetone-d₆/300 MHz) 7.89 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H, J=8.3 Hz),6.99 (d, 1H, J=8.3 Hz), 5.80 (q, 1H, J=7.3 Hz), 4.59 (s, 2H). FABLRMSm/z 275 (M+H). EIHRMS m/z 274.0417 (M+, Calc'd 274.0453). Anal. Calc'dfor C₁₂H₉F₃O₄: C, 52.57; H, 3.31. Found: C, 52.43; H, 3.34.

EXAMPLE 81

6-(Difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Ethyl 6-formyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example75, Step 1)(1.672 g, 5.569 mmol) in methylene chloride (1.5 mL) wasadded to methylene chloride (1.5 mL) and diethylaminosulfur trifluoride(DAST) (0.74 mL, 0.898 g, 5.569 mmol) over 0.07 hours via syringe. Afterstirring for 20 hours the reaction was poured into aqueous HCl (2.0 N)and the mixture was extracted with diethyl ether. The ethereal phase waswashed with dilute aqueous HCl (2.0 N), saturated NaHCO₃ solution,brine, dried over MgSO₄, filtered and concentrated in vacuo yielding aclear colorless oil. This oil was purified by flash chromatography(Silica gel 60, Eluant (5:1; Hexanes:Ethyl Acetate) yielding ethyl6-difluoromethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (0.96g, 54%) as an oil which solidified upon standing. This product was ofsufficient purity to be used in the next step without furtherpurification: ¹H NMR (acetone-d₆/300 MHz) 7.97 (s, 1H), 7.74 (s, 1H),7.65 (d, 1H, J=8.5 Hz), 7.18 (d, 1H, J=8.5 Hz), 6.90 (t, 1H, J=56.0 Hz),5.94 (q, 1H, J=7.0 Hz), 4.40–4.25 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).

Step 2. Preparation of6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

Aqueous NaOH (1.31 mL, 3.277 mmol, 2.5 M solution) was added in oneportion to the ester (Step 1) (0.880 g, 2.731 mmol) in THF:EtOH:H₂O(7:2:1, 10 mL). The resulting solution was stirred for 60 hours. Thereaction mixture was partially concentrated in vacuo to remove theorganic solvents and was diluted with H₂O. The resulting aqueoussolution was washed with diethyl ether, sparged with nitrogen to removetrace ether, and acidified with concentrated HCl. The resulting oilysuspension was extracted with diethyl ether. The combined organic phaseswere dried over MgSO₄, filtered and concentrated in vacuo yielding thetitle compound (0.483 g, 60%) as an oil which solidified as a whitecrystalline mass: mp 134.7–136.2° C. ¹H NMR (acetone-d₆/300 MHz) 7.97(s, 1H), 7.73 (s, 1H), 7.67 (dd, 1H, J=8.5, 1.0 Hz), 7.17 (d, 1H, J=8.5Hz), 6.89 (t, 1H, J=56.2 Hz), 5.90 (q, 1H, J=7.1 Hz). FAB-ESLRMS m/z 293(M−H). EIHRMS m/z 293.0235 (M−H, Calc'd 293.0237). Anal. Calc'd forC₁₂H₇F₅O₃: C, 49.0; H, 2.40. Found: C, 48.78; H, 2.21.

EXAMPLE 82

2,6-Bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of Ethyl2,6-bis(trifluoromethyl)-4-oxo-4H-1-benzopyran-3-carboxylate.

To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22 mL,4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodiumhydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol) causing gasevolution. After gas evolution has subsided,2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.00 g, 22.07 mmol) wasadded. The reaction was stirred at room temperature for 24 hours, thenheated to 105° C. for 24 hours. After cooling to room temperature, thereaction was diluted with diethyl ether and the resulting solution waswashed with H₂O and brine, dried over MgSO₄, filtered and concentratedin vacuo yielding a slightly sticky white solid. This solid wastriturated with hexanes yielding the desired ester(3.05 g, 39%) as awhite powder: mp 116–120.1° C. ¹H NMR (CDCl₃/300 MHz) 8.52 (d, 2H, J=1.6Hz), 8.03 (dd, 1H, J=8.9, 2.2 Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H,J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'dfor C₁₄H₈F₆O₄: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.

Step 2. Preparation of ethyl2,6-bis(trifluoromethyl)-4-oxo-dihydrobenzopyran-3-carboxylate.

A 250 mL round bottom flask was charged with ethyl2,6-bis(trifluoromethyl)-benzopyran-4-one-3-carboxylate (Step 1)(2.307g, 6.513 mmol) and THF (20 mL) yielding a pale yellow solution. Ethanol(20 mL) was added and the reaction chilled in an ice-salt bath. Whilemaintaining the reaction temperature at below 9° C., NaBH₄ (0.246 g,6.513 mmol) was added in two portions and the mixture stirred 1 h. Thecrude reaction mixture was poured into a vigorously stirred mixture ofice (200 mL) and concentrated HCl (12 N, 5 mL) yielding a precipitate.Vacuum filtration of the resulting suspension yielded the desired ketoester (2.204 g, 87%) as faint pink powder of suitable purity to use inthe next step without further purification: mp 71.8–76.9° C. ¹H NMR(acetone-d₆/300 MHz) 12.71 (br s, 1H exch), 8.01 (d, 1H, J=2.0 Hz), 8.01(d, 1H, J=2.0 Hz), 7.88 (dd, 1H, J=8.7, 1.8 Hz), 7.31 (d, 1H, J=8.7 Hz),5.98 (q, 1H, J=6.6 Hz), 4.51–4.28 (m, 2H), 1.35 (t, 3H, J=7.0 Hz).FABLRMS m/z 355 (M−H). ESHRMS m/z 355.0394 (M−H, Calc'd 355.0405). Anal.Calc'd for C₁₄H₁₀F₆O₄: C, 47.21; H, 2.83. Found: C, 47.31; H, 2.97.

Step 3. Preparation of ethyl2,6-bis(trifluoromethyl)-4-trifluoromethanesulfonato-2H-1-benzopyran-3-carboxylate.

A 50 mL 3-neck Morton flask fitted with addition funnel, 2 stoppers wascharged with 2.6-di-tert-butylpyridine (1.576 g, 1.50 mmol), methylenechloride (12 mL), and then via syringe was addedtrifluoromethanesulfonic anhydride (1.08 mL, 1.80 g, 1.25 mmol). To thissolution was added dropwise a solution the keto ester (Step 2) (1.822 g,5.115 mmol) in methylene chloride (10 mL) over 0.33 h and the reactionstirred for 48 h. The resulting off-white suspension was transferred toa 100 mL round bottom flask and was concentrated in vacuo. The residuewas suspended in diethyl ether (50 mL) and vacuum filtered to removesalts. The filtrate was further diluted with diethyl ether (50 mL) andwas washed with ice cold HCl solution (2 N), brine, and dried overNa₂CO₃, filtered and concentrated in vacuo yielding the desired triflate(1.64 g, 66%) as a tan clumpy powder of suitable purity to use in thenext step without further purification.

Step 4. Preparation of ethyl2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A 25 mL pear flask was charged with LiCl (0.136 g, 3.219 mmol), affixedto a high vacuum line and heated with a heat gun removing superficialwater. The flask was allowed to cool to room temperature, andtetrakis(triphenylphosphine)palladium(0) (0.124 g, 0.107 mmol) and THF(2 mL) were added. A reflux condenser was affixed to the flask and theapparatus was purged with nitrogen. A solution of the triflate(Step 3)(0.524 g, 1.073 mmol) in THF (2 mL) and tri-n-butyltin hydride (0.32 mL,0.34 g, 1.18 mmol) were added sequentially via syringe. The resultinglight orange solution was heated to 50° C. with stirring for 1 h, 60° C.for one hour, and 65° C. for one hour. The reaction was allowed to coolto room temperature and was poured into 2 N HCl, stirred, and extractedwith hexanes. The hexane phase was dried over MgSO₄, filtered andconcentrated yielding a light brown oil. The oil was dissolved in hexaneand was washed with aqueous ammonium fluoride solution. The resultinghexane phase was dried over MgSO₄, filtered and concentrated in vacuoyielding a dull yellow oily solid which solidified as a flaky powder(0.443 g). This solid was purified by flash silica chromatography(eluant: hexanes-methylene chloride, 4:1) yielding ethyl2,6-di-trifluoromethyl-2H-1-benzopyran-3-carboxylate (0.069 g, 19%) as awhite crystalline solid of suitable purity to proceed with the nextstep.

Step 5. Preparation of2,6-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

To a stirred solution of the ester (Step 4) (0.065 g, 0.191 mmol) inTHF-EtOH-H₂O (7:2:1, 1 mL) was added NaOH solution (0.084 mL, 0.210mmol) in one portion at room temperature and allowed to stir overnight.The reaction was partially concentrated in vacuo yielding a pale yellowclear syrup. The syrup was diluted with water (5 mL) and brine (1 mL)and was washed with diethyl ether (3×5 mL). The resulting aqueous phasewas sparged with nitrogen to remove trace ether. With stirring,concentrated HCl was added to the aqueous phase causing the formation ofa very fine white precipitate. This suspension was extracted withdiethyl ether and the ether dried over Na₂SO₄, filtered, andconcentrated by slow evaporation at atmospheric pressure. The resultingproduct was recrystallized from hexanes and ethyl acetate yielding thetitle compound (0.038 g, 64%) as a fine tan powder: mp 143.5–145.2° C.¹H NMR (acetone-d₆/300 MHz) 11.97–11.67 (br s, 1H), 8.03 (s, 1H), 7.92(s, 1H), 7.77 (d, 1H, J=8.5 Hz), 7.26 (d, 1H, J=8.7 Hz), 5.96 (q, 1H,J=7.0 Hz). FABLRMS m/z 311 (M−H). ESHRMS m/z 311.0107 (M−H, Calc'd311.0143).

EXAMPLE 83

5,6,7-Trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

3,4,5-Trichlorophenol was converted to 3-ethoxysalicylaldehyde via aprocedure similar to that described in Example 11, Step 1. The4,5,6-trichlrorsalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 236.2–239.3° C. ¹HNMR (acetone-d₆/300 MHz) 8.05 (s, 1H), 7.40 (s, 1H), 5.99 (q, 1H, J=7.0Hz). ESLRMS m/z 345 (M−H). ESHRMS m/z 344.9113 (M−H, Calc'd 344.9100).Anal. Calc'd for C₁₁H₄Cl₃F₃O₃+0.89 wt % H₂O: C, 37.68; H, 1.25; Cl,30.33. Found: C, 37.48; H, 1.25; Cl, 30.33.

EXAMPLE 84

6,7,8-Trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

2,3,4-Trichlorophenol was converted to 3-ethoxysalicylaldehyde via aprocedure similar to that described in Example 11, Step 1. The3,4,5-trichlrorsalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 222.0–225.3° C. ¹HNMR (acetone-d₆/300 MHz) 7.94 (s, 1H), 7.78 (s, 1H), 6.07 (q, 1H, J=7.0Hz). ESLRMS m/z 345 (M−H). EIHRMS m/z 344.9117 (M−H, Calc'd 344.9100).Anal. Calc'd for C₁₁H₄Cl₃F₃O₃+1.56 wt % H₂O: C, 37.43; H, 1.32; Cl,30.13. Found: C, 37.79; H, 0.93; Cl, 29.55.

EXAMPLE 85

7-Ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

3-Ethylphenol was converted to the title compound by a procedure similarto that described in Example 2.: mp 167.0–168.6° C. ¹H NMR (CDCl₃/300MHz) 7.84 (s, 1H), 7.15 (d, 1H, J=7.5 Hz), 6.84 (m, 2H), 5.66 (q, 1H,J=6.8 Hz), 2.63 (q, 2H, J=7.7 Hz, J=7.7 Hz), 1.24 (t, 3H, J=7.7 Hz).Anal. Calc'd for C₁₃H₁₁F₃O₃: C, 57.36; H, 4.07. Found: C, 57.25; H,4.10.

EXAMPLE 86

6-(Methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Ethyl 6-(methylthio)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 2, Step 2) (1.014 g, 3.18 mmol) in methylene chloride waschilled to −50° C. (dry ice acetone). With stirring,meta-chloroperbenzoic acid (0.91 g of 60% reagent, 3.18 mmol) was addedand reaction allowed to proceed for 3 hours. Aqueous NaHSO₃ solution (40mL 0.25 M) was poured into the reaction. More methylene chloride wasadded and the layers mixed, then separated. The organic phase was washedwith aqueous NaHSO₃ solution, aqueous saturated NaHCO₃ solution, brine,dried over MgSO₄, filtered and concentrated yielding an oil. The oil wasdiluted with isooctane (2 mL) and concentrated yielding an oil whichupon standing crystallized. Hexanes was added, the solution was heated,and methylene chloride added until partial dissolution occurred. Aftercooling and standing overnight the suspension was vacuum filteredyielding the sulfoxide substituted ethyl ester (0.753 g, 71%) as whiteneedles: mp 92.2–98.4° C. This ester was of sufficient purity to be usedwithout further purification.

Step 2. Preparation of6-(methylsulfinyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

To a stirred solution of the ester (Step 1) (0.683 g, 2.043 mmol) inTHF:EtOH:H₂O (7:2:1, 4 mL) was added aqueous NaOH solution (0.98 mL of2.5 M, 2.45 mmol). After stirring 12 hours, the reaction was partiallyconcentrated in vacuo to remove the organic solvents. The residue wasdiluted with H₂O, washed with diethyl ether, sparged with nitrogen toremove trace diethyl ether, and acidified with concentrated HCl yieldinga oily suspension. The suspension was extracted with diethyl ether, andthe resulting organic phase dried over MgSO4, filtered, and diluted withhexanes. Upon concentration in vacuo the title acid was obtained as asticky white powder (0.425 g, 68%): mp 148.3–151.0° C. ¹H NMR(acetone-d₆/300 MHz) 7.99 (s, 1H), 7.82 (s, 1H), 7.78–7.68 (m, 1H), 7.24(d, 1H, J=8.3 Hz), 5.92 (q, 1H, J=7.1 Hz), 2.73 (s, 3H). FABLRMS m/z 307(M+H). ESHRMS m/z 305.0098 (M−H, Calc'd 305.0095). Anal. Calc'd forC₁₂H₉F₃O₄S₁: C, 47.06; H, 2.96; S, 10.47. Found: C, 46.69; H, 2.86; S,10.45.

EXAMPLE 87

5,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

2,5-Dichlorophenol was converted to 3,6-dichlorosalicylaldehyde via aprocedure similar to that described in Example 2, Step 1. The3,6-dichlorosalicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 11, Steps 2 & 3: mp205.7–207.1° C. ¹H NMR (acetone-d₆/300 MHz) 8.02 (s, 1H), 7.53 (d, 1H,J=8.7 Hz), 7.22 (d, 1H, J=8.7 Hz), 6.04 (q, 1H, J=7.1 Hz). FABLRMS m/z311 (M−H). ESHRMS m/z 310.9506 (M−H, Calc'd 310.9490). Anal. Calc'd forC₁₁H₅Cl₂F₃O₃+0.63 wt % H₂O: C, 41.94; H, 1.67. Found: C, 41.54; H, 1.27.

EXAMPLE 88

6-(Pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Potassium pentafluoropropionate (0.476 g, 2.35 mmol) was dissolved intoluene (6 mL) and DMF (6 mL). The vessel was fitted with a distillinghead, and CuI (0.471 g, 2.474 mmol) was added with stirring. Thereaction was heated to 120° C., removing the toluene by distillation.Ethyl 6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example72, Step 3) (0.469 g, 1.178 mmol) was added and the reaction was heatedto 150° C. for 2 hours. The reaction was allowed to cool to roomtemperature and was partitioned between diethyl ether and H₂O. Theorganic phase was dried over MgSO₄, filtered and concentrated in vacuo.The resulting residue was purified by flash chromatography (silica gel60, eluant:hexanes-ethyl acetate, 8:1) yielding, upon concentration ofthe solution, the desired ester (0.096 g, 21%) as a tan solid mass ofsuitable purity to use without further purification: ¹H NMR(acetone-d₆/300 MHz) 8.04 (s, 1H), 7.91 (d, 1H, J=2.2 Hz), 7.74 (dd, 1H,J=8.7, 2.2 Hz), 6.00 (q, 1H, J=7.1 Hz), 4.42–4.24 (m, 2H), 1.34 (t, 3H,J=7.3 Hz)

Step 2. Preparation of6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

To a stirred solution of the ethyl ester (Step 1) (0.090 g, 0.231 mmol)in THF:EtOH:H₂O (7:2:1) (4 mL) was added aqueous NaOH solution (0.11 mL,2.5 M). After stirring 16 hours, the reaction was partially concentratedin vacuo to remove the organic solvents, diluted with H₂O, and washedwith diethyl ether. The resulting aqueous phase was acidified withconcentrated HCl, extracted with diethyl ether, dried over MgSO₄,filtered and concentrated in vacuo yielding an oil. The oil was purifiedby flash chromatography (silica, hexanes-ethyl acetate, 3:1 with 5%acetic acid). This procedure yielded the title acid (0.020 g, 24%) as awhite powder: mp 162.3–164.7° C. ¹H NMR (acetone-d₆/300 MHz) 8.05 (s,1H), 7.90 (s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=8.7 Hz), 5.97(q, 1H, J=6.8 Hz). FABLRMS m/z 361 (M−H). ESHRMS m/z 361.0111 (M−H,Calc'd 361.0094).

EXAMPLE 89

6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

4-tert-Butylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 170.6–173.2° C. ¹H NMR(acetone-d₆/300 MHz) 7.89 (s, 1H), 7.5–7.4 (m, 2H), 6.93 (d, 1H, J=8.4Hz), 5.76 (q, 1H, J=7.2 Hz), 1.3 (s, 9H). Anal. Calc'd for C₁₅H₁₅O₃F₃:C, 60.00; H, 5.04. Found: C, 59.93; H, 5.12.

EXAMPLE 90

5-(Hydroxymethyl)-8-methyl-2-(trifluoromethyl)-2H-pyrano[2,3-c]pyridine-3-carboxylicacid

3-Hydroxylmethyl-5-methyl-4-formylpyridine was converted to the titlecompound by a procedure similar to that described in Example 1: mp76.1–80.1° C. ¹H NMR (acetone-d₆/300 MHz) 8.15 (s, 2H), 5.93 (q, 1H,J=7.2 Hz), 1.3 (s, 9H) 5.30 (br s, 1H), 4.79 (br s, 1H), 2.41 (s, 3H).ESHRMS m/z 288.0485 (M+H, Calc'd 288.0483).

EXAMPLE 91

2-(Trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzopyran-3-carboxylicacid

4-(Trifluoromethoxy)phenol was converted to5-(trifluoromethoxy)salicylaldehyde via a procedure similar to thatdescribed in Example 2, Step 1. The 5-(trifluoromethoxy)salicylaldehydewas converted to the title compound by a similar procedure to thatdescribed in Example 11, Steps 2 & 3: mp 139.1–143.2° C. ¹H NMR(acetone-d₆/300 MHz) 7.95 (s, 1H), 7.88 (d, 2H, J=2.4 Hz), 7.71–7.75 (m,1H), 6.93 (d, 1H, J=8.7 Hz), 5.91 (q, 1H, J=6.9 Hz). Anal. Calc'd forC₁₂H₆O₃F₃S: C, 41.87; H, 1.76. Found: C, 41.94; H, 1.84.

EXAMPLE 92

6-(Trifluoromethyl)-6H-1,3-dioxolo[4,5-g][1]benzopyran-7-carboxylic acid

4-tert-Butylphenol was converted to the title compound by a proceduresimilar to that described in Example 2: mp 245.8–247.8° C. ¹H NMR(acetone-d₆/300 MHz) 7.77 (s, 1H), 6.95 (s, 1H), 6.12 (s, 1H), 6.05 (d,2H, J=0.90 Hz), 5.91 (q, 1H, J=7.2 Hz). Anal. Calc'd for C₁₂H₇O₅F₃: C,50.01; H, 2.45. Found: C, 50.02; H, 2.50.

EXAMPLE 93

8-Ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

2-Ethoxyphenol was converted to 3-ethoxysalicylaldehyde via a proceduresimilar to that described in Example 11, Step 1. The3-ethoxysalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 159.4–160.9° C. ¹HNMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 6.97–7.14 (m, 3H), 5.83(q_(H-F′)1H, J=7.2 Hz), 4.12 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz).FABHRMS m/z 289.0656 (M+H, Calc'd 289.0686). Anal. Calc'd forC₁₃H₁₁F₃O₄: C, 54.17; H, 3.85. Found: C, 54.06; H, 3.83.

EXAMPLE 94

6-Chloro-2,7-bis(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

4-Chloro-3-(trifluoromethyl)phenol was converted to the title compoundby a procedure similar to that described in Example 11: mp 180.9–182.4°C. ¹H NMR (acetone-d₆/300 MHz) 7.96 (s, 1H), 7.84 (s, 1H), 7.47 (s, 1H),5.96 (q, 1H, J=6.8 Hz), 2.50 (s, 3H). FABLRMS m/z 345 (M−H). FABHRMS m/z344.9767 (M−H, Calc'd 344.9753). Anal. Calc'd for C₁₂H₅ClF₆O₃: C, 41.58;H, 1.45; Cl, 10.23. Found: C, 41.57; H, 1.50; Cl, 10.33.

EXAMPLE 95

5-Methoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

6-Methoxysalicylaldehyde was converted to the title compound by asimilar procedure to that described in Example 11, Steps 2 & 3: mp204.5–206.7° C. ¹H NMR (acetone-d₆/300 MHz) 8.08 (s, 1H), 7.38 (dd, 1H,J=8.5 Hz 8.3 Hz), 6.74 (d, 1H, J=8.5 Hz), 6.65 (d, 1H, J=8.3 Hz), 5.80(q, 1H, J=7.2 Hz), 3.94 (s, 3H). FABLRMS m/z 273 (M−H). EIHRMS m/z274.0444 (M+, Calc'd 274.0453). Anal. Calc'd for C₁₂H₉F₃O₄: C, 52.57; H,3.31. Found: C, 52.47; H, 3.34.

EXAMPLE 96

6-Benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-benzoyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 10,Step 1) (1.59 g, 5.8 mmol) was dissolved in; 1,2-dichloroethane (3 mL)and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol)in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g,7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction washeated to 80° C. and stirred for 4 hours. The solution was poured onto 3N HCl and ice and extracted with ethyl acetate. The ethyl acetate layerswere combined, washed with 3N HCl saturated sodium bicarbonate, brine,dried over MgSO₄ and concentrated in vacuo. The crude ester was purifiedby flash chromatography over silica gel (with 1:9 ethyl acetate/hexaneas eluant) to afford the ester as a white crystalline solid (0.26 g,12%): mp 114.7–116.1° C. ¹H NMR (CDCl₃/300 MHz) 7.82 (dd, 1H, J=8.5 Hz2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).

Step 2. Preparation of6-benzoyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

The ester from Step 1 (0.24 g, 0.64 mmol) was dissolved in THF (2 mL)and ethanol (2 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8mmol), and stirred at room temperature for 4.3 hours. The reactionmixture was concentrated in vacuo, acidified with 3N HCl yielding asolid. The solid was collected by filtration and was recrystallized fromethanol-water to yield a white solid (0.14 g, 64%): mp 269.8–270.8° C.¹H NMR (acetone-d₆/300 MHz) 8.04 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.88(dd, 1H, J=8.5 Hz 2.0 Hz), 7.79 (m, 2H), 7.68 (m, 1H), 7.57 (m, 1H),7.23 (d, 1H, J=8.6 Hz), 5.98 (q, 1H, J=7.0 Hz). FABLRMS m/z 347 (M−H).ESHRMS m/z 347.0560 (M−H, Calc'd 347.0531). Anal. Calc'd forCl₁₈H₁₁F₃O₄: C, 62.08; H, 3.18. Found: C, 61.48; H, 3.22.

EXAMPLE 97

6-(4-Chlorobenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared analogous to theprocedure described in Example 96: mp 268.3–269.4° C. ¹H NMR(acetone-d₆/300 MHz) 8.03 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.89 (dd, 1H,J=8.5 Hz, 2.0 Hz), 7.81 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=8.5 Hz), 7.23(d, 1H, J=8.5 Hz), 5.98 (q, 1H, J=7.1 Hz). FABLRMS m/z 381 (M−H). ESHRMSm/z 381.0135 (M−H, Calc'd 381.0141). Anal. Calc'd for C₁₈H₁₀ClF₃O₄: C,56.49; H, 2.63; Cl, 9.26. Found: C, 56.35; H, 2.66; Cl, 9.34.

EXAMPLE 98

6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared analogous to theprocedure described in Example 96: mp 234.0–239.5° C. ¹H NMR(acetone-d₆/300 MHz) 8.03 (s, 1H), 7.92 (d, 1H, J=2.0 Hz), 7.83 (dd, 1H,J=8.5 Hz 2.0 Hz), 7.74 (d, 2H, J=8.7 Hz), 7.20 (d, 1H, J=8.5 Hz), 7.00(d, 1H, J=8.7 Hz), 5.94 (q, 1H, J=7.1 Hz). ESHRMS m/z 363.0471 (M−H,Calc'd 363.0480).

EXAMPLE 99

6-Phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

4-Phenoxyphenol was converted to 5-phenoxysalicylaldehyde by a similarprocedure to that described in Example 2, Step 1.5-Phenoxysalicylaldehyde was converted into the title compound by asimilar procedure to that described in Example 11, Steps 2 & 3: mp184.9–186.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.39 (m, 2H),7.20 (d, 1H, J=2.0 Hz), 7.08 (m, 3H), 7.02 (m, 2H), 5.98 (q, 1H, J=7.2Hz). FABLRMS m/z 335 (M−H). FABHRMS m/z 337.0663 (M+H, Calc'd 337.0687).Anal. Calc'd for C₁₇H₁₁F₃O₄: C, 60.72; H, 3.30. Found: C, 60.62; H,3.29.

EXAMPLE 100

8-Chloro-6-(4-chlorophenoxy)-2-trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of 5-phenoxysalicylaldehyde.

Ethyl magnesium bromide (67.5 mL of an approximately 3.0 M solution indiethyl ether, 202.5 mmol) was added to toluene (50 mL). A solution of4-phenoxyphenol (25.00 g, 134.26 mmol) in diethyl ether (35 mL) wasadded resulting in the evolution of gas. The reaction was heated to 80°C. causing distillation of the diethyl ether. Toluene (300 mL), HMPA(23.4 mL, 24.059 g, 134.26 mmol), and paraformaldehyde (10.07 g, 335.65mmol) were added and the reaction was heated to 85° C. for 4 hours. Thereaction was cooled to room temperature and was acidified with 2N HCl.The resulting layers were separated and the organic phase collected. Theorganic phase was washed with brine. The combined aqueous phases wereextracted with methylene chloride. The organic phases were combined,dried over MgSO₄, filtered and concentrated in vacuo yielding a yellowoil. The oil was purified by silica flash chromatography (hexanes-ethylacetate, 95:5). Concentration in vacuo of the desired fractions providedthe salicylaldehyde as a pale yellow powder (12.0 g, 42%) of suitablepurity to use in subsequent steps.

Step 2. Preparation of 3-chloro-5-(4-chlorophenoxy)salicylaldehyde.

To a stirred solution of the salicylaldehyde (Step 1)(0.981 g, 4.58mmol) in acetic acid (20 mL) was added chlorine gas via a tube until theyellow color of chlorine persisted. After stirring for four hours atroom temperature the reaction was sparged with nitrogen and diluted withwater (50 mL). The resulting oily suspension was extracted withmethylene chloride. The methylene chloride phase was washed with sodiumbisulfite solution, dried over MgSO₄, filtered and concentrated in vacuoproviding the dichlorinated salicylaldehyde as a yellow oil (0.66 g,51%) of suitable purity for use in subsequent steps without furtherpurification.

Step 3. Preparation of ethyl8-chloro-6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A mixture of the dichlorinated salicylaldehyde (Step 2) (0.66 g, 2.3mmol), triethylamine (0.49 g, 4.8 mmol), ethyl 4,4,4-trifluorocrotonate(0.59 g, 3.5 mmol) in dimethyl sulfoxide (5 mL) was heated to 85° C. for3.5 hours. The reaction was allowed to cool to room temperature and wasdiluted with ethyl acetate (50 mL). The resulting mixture was washedwith 3 N HCl (50 mL), aqueous potassium carbonate solution (10 weight %,2×30 mL), and brine. The organic phase was dried over MgSO₄, filteredand concentrated in vacuo yielding a brown oil. This oil was purified byflash silica chromatography (hexanes-ethyl acetate, 9:1) providing thesubstituted 2H-1-benzopyran (0.39 g, 39%) of suitable purity to use insubsequent steps without further purification.

Step 4. Preparation of8-chloro-6-(4-chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

To a solution of the substituted 2H-1-benzopyran ethyl ester (Step 3)(0.37 g, 0.85 mmol) in ethanol-THF (4 mL, 1:1) was added sodiumhydroxide solution (2 mL of 2.5 N, 5 mmol). After stirring for six hoursthe mixture was concentrated in vacuo. Acidification of the mixture with3 N HCl yielded a solid which was collected by vacuum filtration. Thissolid was recrystallized from ethanol-water yielding the title compoundas yellow crystals (0.134 g, 38%): mp 227.8–228.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.93 (s, 1H), 7.42 (d, 2H, J=8.9 Hz), 7.24 (s, 2H),7.12 (d, 2H, J=8.9 Hz), 5.97 (q, 1H, J=7.1 Hz). FABLRMS m/z 403 (M−H).FABHRMS m/z 405.9790 (M+H, Calc'd 405.9801). Anal. Calc'd forC₁₇H₉Cl₂F₃O₄+2.33% H₂O: C, 49.22; H, 2.45. Found: C, 49.19; H, 2.27.

EXAMPLE 101

2-(Trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylicacid

4-(4-Trifluoromethylphenyl)phenol was converted to5-(4-trifluoromethylphenyl)salicylaldehyde via a procedure similar tothat described in Example 2, Step 1. The5-(4-trifluoromethylphenyl)salicylaldehyde was converted to the titlecompound by a similar procedure to that described in Example 11, Steps 2& 3: mp 153.5–154.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.91 (s, 1H), 7.71(d, 2H, J=8.9 Hz), 7.33 (s, 1H, J=2.8 Hz), 7.15 (m, 4H), 5.86 (q, 1H,J=7.1 Hz). FABLRMS m/z 403 (M−H). ESHRMS m/z 403.0399 (M−H, Calc'd403.0405). Anal. Calc'd for C₁₈H₁₀F₆O₄: C, 53.48; H, 2.49. Found: C,53.52; H, 2.55.

EXAMPLE 102

8-(1-Methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

4-(4-Methoxyphenyl)phenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 210.5–211.5° C. ¹HNMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.35 (d, 1H, J=7.7 Hz), 7.28 (s,1H, J=7.5 Hz), 7.04 (t, 1H, J=7.7 Hz), 5.85 (q, 1H, J=7.2 Hz), 3.33(sept, 1H, J=7.1 Hz), 1.25 (d, 6H, J=7.1 Hz). Anal. Calc'd forC₁₄H₁₃F₃O₃: C, 58.74; H, 4.58. Found: C, 58.65; H, 4.60.

EXAMPLE 103

6-Chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

8-(1-Methylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid(Example 6) was converted to the title compound by a procedure similarto that described in Example 9. mp 185.4–189.2° C. ¹H NMR(acetone-d₆/300 MHz) 7.87 (s, 1H), 7.38 (d, 1H, J=2.4 Hz), 7.34 (d, 1H,J=2.4 Hz), 5.90 (q, 1H, J=7.3 Hz), 3.31 (m, 1H), 1.24 (d, 6H, J=6.8 Hz).Anal. Calc'd for C₁₅H₁₄ClF₃O₃: C, 52.43; H, 3.77; Cl, 11.05. Found: C,52.58; H, 3.79; Cl, 10.96.

EXAMPLE 104

6-(4-Chlorophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared from6-phenoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example99) as the starting material by a procedure similar to that described inExample 9: mp 140.5–142.5° C. ¹H NMR (acetone-d₆/300 MHz) 7.90 (s, 1H),7.39 (d, 2H, J=9.1 Hz), 7.25 (d, 1H, J=2.6 Hz) 7.01–7.15 (m, 4H), 5.85(q, 1H, J=7.2 Hz). FABLRMS m/z 370 (M+). ESHRMS m/z 369.0130(M−H, Calc'd369.0141). Anal. Calc'd for C₁₇H₁₀ClF₃O₄+0.96% H₂O: C, 54.55; H, 2.80.Found: C, 54.38; H, 2.90.

EXAMPLE 105

8-Chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-2H-1-benzopyran-3-carboxylicacid

The benzopyran-3-carboxylic acid was prepared using2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1-benzopyran-3-carboxylicacid (Example 101) as the starting material by a similar procedure tothat described in Example 100: mp 223.7–226.0° C. ¹H NMR (acetone-d₆/300MHz) 7.94 (s, 1H), 7.74 (d, 2H, J=8.5 Hz), 7.35 (m, 2H) 7.25 (d, 2H,J=8.5 Hz), 6.00 (q, 1H, J=7.0 Hz). FABLRMS m/z 437 (M−H). ESHRMS m/z437.0000 (M−H, Calc'd 437.0015). Anal. Calc'd for C₁₈H₉ClF₆O₄: C, 49.28;H, 2.07; Cl, 8.08. Found: C, 49.42; H, 2.12; Cl, 8.17.

EXAMPLE 106

3-(Trifluoromethyl)-3H-benzofuro[3,2-f]benzopyran-2-carboxylic acid

2-Hydroxydibenzofuran was converted to the title compound by a proceduresimilar to that described in Example 2: mp 253.5–254.6° C. ¹H NMR(acetone-d₆/300 MHz) 8.54 (s, 1H), 8.23 (d, 1H, J=7.5 Hz), 7.71 (s, 1H),7.62 (m, 1H), 7.50 (m, 1H), 7.23 (d, 1H, J=8.9 Hz), 5.95 (q, 1H, J=7.3Hz). FABLRMS m/z 333 (M−H). ESHRMS m/z 333.0401 (M−H, Calc'd 333.0375).Anal. Calc'd for C₁₇H₉F₃O₄: C, 61.09; H, 2.71. Found: C, 60.95; H, 2.80.

EXAMPLE 107

6-Chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-chloro-8-(hydroxyiminomethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Hydroxylamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate (1.50 g,19.4 mmol), and a mixture of ethanol-water (80:20, 15 mL) were stirredat room temperature for 0.4 hours. The aldehyde (Example 76, Step3)(3.07 g, 9.0 mmol) was dissolved in a solution of ethanol-water (4:1,25 mL) and added to this mixture and stirred at 100° C. for 1 hour. Thereaction was filtered hot and the filtrate allowed to cool to roomtemperature. An orange solid crystallized in the filtrate which wascollected by vacuum filtration. The solid was dissolved in ethyl acetateand the solution washed with water, brine, dried over MgSO₄,concentrated in vacuo. The resulting solid was recrystallized from ethylacetate-hexane yielding the oxime as a tan powder (1.50 g, 47%): mp186.6–187.6° C. ¹H NMR (acetone-d₆/300 MHz) 10.87 (s, 1H), 8.34 (s, 1H),7.90 (s, 1H), 7.77 (d, 1H, J=2.6 Hz), 7.60 (d, 1H, J=2.6 Hz), 6.02 (q,1H, J=7.1 Hz), 4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).

Step 2. Preparation of ethyl6-chloro-8-cyano-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate.

The oxime from Step 1 (0.61 g, 1.7 mmol) and acetic anhydride (6 mL)were stirred at 140° C. for 6.3 hours. The reaction was poured intowater, extracted with ethyl acetate, washed with saturated NaHCO₃,brine, dried over MgSO₄, and concentrated in vacuo to give a brown oil(1.09 g). The oil was purified by flash chromatography (10:1; hexanes:ethyl acetate) yielding upon concentration the title compound as a whitesolid (0.51 g, 88%): mp 114.6–115.6° C. ¹H NMR (CDCl₃/300 MHz) 7.65 (s,1H), 7.53 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.87 (q, 1H, J=6.4Hz), 4.36 (m, 2H), 1.37 (t, 3H, J=6.5 Hz).

Step 3. Preparation of6-chloro-8-cyano-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.

The ester from Step 2 (0.51 g 1.5 mmol) was dissolved in THF (5 mL) andethanol (5 mL), treated with 2.5N sodium hydroxide (1.2 mL, 3.0 mmol),and stirred at room temperature for 1.5 hours. The reaction mixture wasconcentrated in vacuo, acidified with 3N HCl extracted with ethylacetate, washed with water, brine, dried over MgSO₄, concentrated invacuo, and recrystallized from diethyl ether/hexane to give a whitepowder (0.10 g, 21%): mp 238.1–239.7° C. ¹H NMR (acetone-d₆/300 MHz)7.97 (s, 1H), 7.92 (d, 1H, J=2.4 Hz), 7.89 (d, 1H, J=2.4 Hz), 6.14 (q,1H, J=6.6 Hz). FABLRMS m/z 302 (M−H). ESHRMS m/z 301.9819 (M−H, Calc'd301.9832). Anal. Calc'd for C₁₂H₅ClF₃NO₃: C, 47.47; H, 1.66; N, 4.61.Found: C, 47.41; H, 1.70; N, 4.55.

EXAMPLE 108

6-Chloro-8-[(hydroxyimino)methyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared from the ethyl ester(Example 107, Step 2) by a method similar to the procedure described inExample 1, Step 2: mp 246.9–247.9° C. ¹H NMR (acetone-d₆/300 MHz) 10.90(brs, 1H), 8.35 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H, J=2.6 Hz), 7.61 (d,1H, J=2.6 Hz), 5.98 (q, 1H, J=7.0 Hz). FABLRMS m/z 320 (M−H). ESHRMS m/z319.9959 (M−H, Calc'd 319.9937). Anal. Calc'd for C₁₂H₇ClF₃NO₄: C,44.81; H, 2.19; N, 4.35. Found: C, 44.92; H, 2.25; N, 4.26.

EXAMPLE 109

6-Chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 80 using the carboxylic acid(Example 76, step 4) as the starting material: mp 174.6–178.9° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.57 (d, 1H, J=2.6 Hz), 7.47 (d, 1H,J=2.6 Hz), 5.87 (q, 1H, J=7.0 Hz), 4.70 (s, 2H). FABLRMS m/z 309 (M+H).ESHRMS m/z 306.9981 (M−H, Calc'd 306.9985). Anal. Calc'd forC₁₂H₈ClF₃O₃(3.81 wt. % H₂O): C, 47.37; H, 3.08. Found: C, 47.33; H,2.82.

EXAMPLE 110

8-(1H-Benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl8-(1H-Benzimidazol-2-yl)-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A solution of the aldehyde (Example 76, Step 3)(0.33 g, 0.99 mmol) and1,2-phenylenediamine (0.11 g, 1.02 mmol) in nitrobenzene (20 mL) washeated to 150° C. for 1.8 hours. The reaction mixture was extracted withethyl acetate, washed with brine, dried over MgSO₄, and concentrated invacuo and purified by flash chromatography over silica gel (with 1:9ethyl acetate/hexane as eluant) to give the ester as a brown solid (0.18g, 43%) which was used in the next step without further purification.

Step 2. Preparation of8-(1H-enzimidazol-2-yl)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid.

The ester from Step 1 (0.18 g 1.5 mmol) was dissolved in THF (5 mL) andethanol (5 mL), treated with 2.5 N sodium hydroxide (2.6 mL, 6.5 mmol),and stirred at room temperature for 1.7 hours. The reaction mixture wasconcentrated in vacuo, acidified with 3 N HCl filtered andrecrystallized from ethanol-water to give a tan solid (0.09 g, 52%):mp>300° C. ¹H NMR (acetone-d₆/300 MHz) 8.59 (d, 1H, J=2.6 Hz), 8.03 (s,1H), 7.73 (d, 1H, J=2.6 Hz), 7.67 (brs, 2H), 7.28 (m, 2H), 6.13 (q, 1H,J=6.8 Hz). FABLRMS m/z 395 (M−H{³⁷Cl}). ESHRMS m/z 393.0262 (M−H, Calc'd393.0254). Anal. Calc'd for C₁₈H₁₀ClF₃N₂O₃ (2.88 wt % H₂O): C, 53.19; H,2.80; N, 6.89. Found: C, 53.22; H, 2.90; N, 6.80.

EXAMPLE 111

7-(1,1-Dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl 3-hydroxy-4,4,5,5,5-pentafluoropentanoate.

A solution of ethyl 4,4,5,5,5-pentafluoro-3-oxo-pentanoate (41.32 g,0.18 mole) in diethyl ether (70 mL) was cooled to 0° C. and treated withNaBH₄ (7.09 g, 0.19 mole). The reaction was allowed to warm to roomtemperature and stirred for 2 hours before quenching with 1 N HCl (200mL). The layers were separated and the aqueous layer was extracted withdiethyl ether. The combined organic layers were washed with 1 N HCl,brine, dried over MgSO₄, and concentrated in vacuo to give the hydroxyester as a clear oil (46.40 g) which was used in the next step withoutfurther purification.

Step 2. Preparation of ethyl 4,4,5,5,5-pentafluoro-2-pentenoate.

The hydroxy ester from Step 1 (46.40 g, 0.18 mole) was stirred at 120°C. with P₂O₅ (25.59 g, 0.09 mole) for 2.6 hours then vacuum distilled(95 torr, 45–64° C.) to give the ester as a clear oil (13.70 g, 35%): ¹HNMR (CDCl₃/300 MHz) 6.78 (m, 1H), 6.57 (dt, 1H, J=15.9 Hz 2.0 Hz), 4.30(q, 2H, J=7.3 Hz), 1.34 (t, 3H, J=7.1 Hz).

Step 3. Preparation of ethyl7-(1,1-Dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylate.

A mixture of 4-tert-butylsalicylaldehyde Example 8, step 1 (1.15 g, 6.4mmol) and the ethyl ester from Step 2 (1.59 g, 7.3 mmol) was dissolvedin anhydrous DMF (4 mL). With stirring, K₂CO₃ (1.10 g, 9.0 mmol) wasadded causing the reaction to become deep red. The reaction was stirredat room temperature for 100 hours, acidified with 3 N HCl, diluted withethyl acetate and washed with saturated NaHCO₃ solution, brine, driedover MgSO₄, filtered and concentrated in vacuo yielding a brown oil.This oil was purified by flash chromatography over silica gel, elutingwith 10% ethyl acetate/hexanes to afford a yellow oil (1.72 g, 70%): ¹HNMR (CDCl₃/300 MHz) 7.76 (s, 1H), 7.14 (d, 1H, J=8.1 Hz), 7.04 (dd, 1H,J=8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, J=22.4 Hz 3.0 Hz), 4.32(m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.30 (s, 9H).

Step 4. Preparation of7-(1,1-Dimethylethyl)-2-(pentafluoroethyl)-2H-1-benzopyran-3-carboxylicacid.

The ester from Step 3 (1.58 g 4.20 mmol) was dissolved in THF (3 mL) andethanol (3 mL), treated with 2.5 N sodium hydroxide (2 mL, 5 mmol), andstirred at room temperature for 23.3 hours. The reaction mixture wasconcentrated in vacuo, acidified with 3 N HCl yielding a suspension. Thesolid was collected by filtration and was recrystallized fromethanol-water to yield a yellow solid (0.76 g, 52%): mp 171.0–173.5° C.¹H NMR (acetone-d₆/300 MHz) 7.93 (s, 1H), 7.39 (d, 1H, J=8.1 Hz), 7.18(dd, 1H, J=8.1 Hz 1.8 Hz), 7.02 (s, 1H), 6.01 (dd, 1H, J=23.1 Hz 3.2Hz), 1.32 (s, 9 H). FABLRMS m/z 351 (M+H). EIHRMS m/z 350.0945 (M+,Calc'd 350.0941). Anal. Calc'd for C₁₆H₁₅F₅O₃: C, 54.86; H, 4.32. Found:C, 54.88; H, 4.32.

EXAMPLE 112

6-Chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A suspension of the aldehyde (Example 75, Step 1) (4.78 g, 14.3 mmol)was cooled to 0° C. and treated with NaBH₄ (0.33 g, 4.8 mmol). Thesolution was stirred for 10 minutes then quenched with 3N HCl, extractedwith ethyl acetate, washed with saturated NaHCO₃, brine, dried overMgSO₄, and concentrated in vacuo to give a brown solid which wasfiltered through a plug of silica gel to give the alcohol as a brownsolid (3.60 g, 75%). ¹H NMR (CDCl₃/300 MHz) 7.66 (s, 1H), 7.41 (d, 1H,J=2.4 Hz), 7.17 (d, 1H, J=2.4 Hz), 5.75 (q, 1H, J=6.8 Hz), 4.71 (s, 2H),4.33 (m, 2H), 1.85 (brs, 1H), 1.36 (t, 3H, J=7.1). This solid was usedin the next step without further purification.

Step 2. Preparation of ethyl6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

The alcohol from Step 1 (0.44 g, 1.3 mmol), silver triflate (0.36 g, 1.4mmol) and 2,6-di-tert-butylpyridine (0.37 g, 1.9 mmol) were dissolved inmethylene chloride (3 mL) cooled to 0° C. and treated with methyl iodide(0.40 g, 2.8 mmol). The reaction was allowed to warm and stirred at roomtemperature for 4.6 hours. The reaction was filtered throughdiatomaceous earth and the filtrate was washed with 3N HCl, saturatedNaHCO₃, brine, dried over MgSO₄, and concentrated in vacuo yielding abrown oil. This oil was purified by flash chromatography over silicagel, eluting with 10% ethyl acetate-hexanes to afford the substituted2H-1-benzopyran (0.19 g, 41%) as a white oily solid suitable for usewithout further purification. ¹H NMR (CDCl₃/300 MHz) 7.63 (s, 1H), 7.39(d, 1H, J=2.6 Hz), 7.13 (d, 1H, J=2.6 Hz), 5.72 (q, 1H, J=6.8 Hz), 4.44(m, 2H), 4.30 (m, 2H), 3.41 (s, 3H), 1.85 (brs, 1H), 1.33 (t, 3H,J=7.1).

Step 3. Preparation of6-chloro-8-(methoxymethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid.

The ester from Step 2 was hydrolyzed via a procedure similar to thatdescribed in Example 1, Step 2. mp 166.7–168.0° C. ¹H NMR(acetone-d₆/300 MHz) 7.90 (s, 1H), 7.50 (d, 1H, J=2.6), 7.46 (d, 1H,J=2.4 Hz), 5.92 (q, 1H, J=7.1 Hz), 4.49 (s, 2H), 3.42 (s, 3H). FABLRMSm/z 321 (M−H). ESHRMS m/z 321.0141 (M−H, Calc'd 321.0141). Anal. Calc'dfor C₁₃H₁₀ClF₃O₄: C, 48.39; H, 3.12. Found: C, 48.45; H, 3.11.

EXAMPLE 113

6-Chloro-8-(benzyloxymethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 112: mp 133.8–135.4° C. ¹HNMR (acetone-d₆/300 MHz) 7.90 (s, 1H), 7.54 (d, 1H, J=2.6), 7.51 (d, 1H,J=2.4 Hz), 7.42 (m, 5H), 5.91 (q, 1H, J=7.1 Hz), 4.68 (s, 2H), 4.63 (s,2H). FABLRMS m/z 399 (M+H). ESHRMS m/z 397.0454 (M−H, Calc'd 397.0461).Anal. Calc'd for C₁₉H₁₃ClF₃O₄: C, 57.23; H, 3.54; Cl, 8.89. Found: C,57.34; H, 3.63; Cl, 8.77.

EXAMPLE 114

6-Chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation ofethenyl-6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

In a 100 mL round bottomed flask under N₂, ethyl8-bromo-6-chloro-2-trifluoromethyl-2H-benzopyran-3-carboxylate (Example74, Step 1)(2.21 g, 5.73 mmol) was dissolved in toluene (30 mL ofanhydrous reagent). Tetrakis (triphenylphosphine)palladium(0) (0.132 g,0.115 mmol) was added, followed by tributylethyenylstannane (2.0 g, 6.31mmol). The resulting solution was heated to reflux for 5 hours. Thereaction mixture was allowed to cool to room temperature, was pouredinto 50 mL of 20% ammonium fluoride solution and stirred for one hour.Diethyl ether (100 mL) was added and the mixture was washed with water(2×50 mL). The organic phase was dried over MgSO₄, filtered, andevaporated to yield a yellow oil. The crude material was purified byflash chromatography (0.5% ethyl acetate in hexanes) to afford the esteras a yellow solid (0.86 g, 45%): mp 75.9–77.2° C. ¹H NMR (CDCl₃/300 MHz)7.64 (s, 1H), 7.45 (d, 1H, J=2.5 Hz), 7.12 (d, 1H, J=2.6 Hz), 6.92 (dd,1H, J=17.7 Hz, 11.3 Hz), 5.81 (d, 1H, J=17.7 Hz), 5.76 (q, 1H, J=6.8Hz), 5.41 (d, 2H, J=11.1 Hz), 4.36–4.29 (m, 2H), 1.36 (t, 3H, J=7.3 Hz).FABLRMS m/z 350.1 (M+NH₄ ⁺). ESHRMS m/z 350.0796 (M+NH₄ ⁺, Calc'd.350.0771). Anal. Calc'd. for C₁₅H₁₂ClF₃O₃+4.07% H₂O: C, 51.95; H, 3.94.Found: C, 51.67; H, 3.69.

Step 2. Preparation of6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

The ester (Step 1) (0.350 g, 1.05 mmol) was dissolved in a solution ofTHF:ethanol:water (7:2:1; 10 mL), was treated with sodium hydroxide(0.46 mL, 1.05 mmol of a 2.5 N solution), and stirred at roomtemperature for 18 hours. The solvent was removed in vacuo and theresidue was dissolved in water (10 mL). Diethyl ether (10 mL) was addedand the mixture acidified with concentrated HCl. The layers wereseparated, and the aqueous phase was extracted with diethyl ether (2×10mL). The organic phases were combined, dried over MgSO₄, filtered, andevaporated to yield a yellow solid, which was recrystallized in diethylether-hexane to afford the title compound as a yellow solid (0.288 g,90%): mp 183.2–185.8° C. ¹H NMR (CDCl₃/300 MHz) 7.77 (s, 1H), 7.49 (d,1H, J=2.2 Hz), 7.16 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=11.3, 17.7 Hz),5.82 (d, 1H, J=17.7 Hz), 5.74 (q, 1H, J=6.9 Hz), 5.43 (d, 1H, J=11.1Hz). FABLRMS m/z 303 (M−H). ESHRMS m/z 303.0014 (M−H, Calc'd.303.003582). Anal. Calc'd. for C₁₃H₈ClF₃O₃+1.58% H₂O: C, 50.44; H, 2.78.Found: C, 50.42; H, 2.65.

EXAMPLE 115

6-Chloro-8-ethynyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 114: mp 186.2–189.0° C. ¹HNMR (acetone-d₆/300 MHz) 7.87 (s, 1H), 7.60 (d, 1H, J=2.4 Hz), 7.51 (d,1H, J=2.4 Hz), 5.95 (q, 1H, J=7.0 Hz), 4.02 (s, 1H). FABLRMS m/z 301(M−H). ESHRMS m/z 300.9875 (M−H, Calc'd 300.9879). Anal. Calc'd. forC₁₃H₆ClF₃O₃: C, 51.59; H, 2.00; Cl, 11.71. Found: C, 51.26; H, 2.06; Cl,11.40.

EXAMPLE 116

6-Chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 114: mp 257.5–258.8° C. ¹HNMR (acetone-d₆/300 MHz) 7.91 (s, 1H), 7.79 (d, 1H, J=2.4 Hz), 7.74–7.72(m, 1H), 7.62–7.61 (m, 1H), 7.51 (d, 1H, J=2.4 Hz), 7.19–7.16 (m, 1H),6.04 :(q, 1H, J=7.1 Hz). FABLRMS m/z 359 (M−H). ESHRMS m/z 358.9747(M−H, Calc'd. 358.975.6). Anal. Calc'd. for C₁₅H₈ClF₃O₃S: C, 49.94; H,2.24; Cl, 9.83; S, 8.89. Found: C, 50.26; H, 2.45; Cl, 9.72; S, 9.00.

EXAMPLE 117

6-Chloro-8-(2-furanyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 114: mp 171.5–173.3° C. ¹HNMR (acetone-d₆/300 MHz) 7.93 (s, 1H), 7.82 (d, 1H, J=2.6 Hz), 7.72–7.71(m, 1H), 7.50 (d, 1H, J=2.6 Hz), 7.16 (d, 1H, J=2.4 Hz), 6.65–6.63 (m,1H), 6.11 (q, 1H, J=7.1 Hz). FABLRMS m/z 343 (M−H). ESHRMS m/z 342.9995(M−H, Calc'd. 342.9985). Anal. Calc'd. for C₁₅H₈ClF₃O₄+1.31% H₂O: C,51.59; H, 2.46; Cl, 10.15. Found: C, 51.57; H, 2.33; Cl, 10.14.

EXAMPLE 118

6-Chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Ethyl 6-chloro-8-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate(Example 73, Step 2) (1.50 g, 3.47 mmol),tetrakis-(triphenylphosphine)palladium(0) (0.2 g, 0.174 mmol),copper(I)iodide (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4mmol) were dissolved in toluene (50 mL). 5-Chloro-1-pentyne (0.53 g,5.20 mmol) was added via syringe and the mixture stirred for 18 hours atroom temperature. The reaction was diluted with diethyl ether (50 mL),extracted with 0.5 N HCl (2×25 mL), and water (2×25 mL). The organicphase was dried over MgSO₄, filtered, and evaporated to yield an orangeoil. The crude material was purified by flash chromatography in 2% ethylacetate in hexane. Recrystallization from hexane afforded the ester as awhite solid (0.96 g, 68%): mp 84.8–85.9° C. ¹H NMR (CDCl₃/300 MHz) 7.61(s, 1H), 7.33 (d, 1H, J=2.6 Hz), 7.14 (d, 1H, J=2.6 Hz), 5.79 (q, 1H,J=6.7 Hz), 4.37–4.29 (m, 2H), 3.75 (t, 2H, J=6.7 Hz), 2.67 (t, 2H, J=6.7Hz), 2.11–2.03 (m, 2H,), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 424.1(M+NH₄ ⁺). ESHRMS m/z 424.0694 (M+NH₄ ⁺, Calc'd. 424.0694). Anal.Calc'd. for C₁₈H₁₅Cl₂F₃O₃: C, 53.09; H, 3.71;, Cl, 17.41. Found: C,53.02; H, 3.90; Cl, 17.63.

Step 2. Preparation of6-chloro-8-(5-chloro-1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

The ester (Step 1) (0.500 g, 1.23 mmol) was dissolved inTHF-ethanol-water (7:2:1; 10 mL). It was treated with sodium hydroxide(0.49 mL, 1.23 mmol of a 2.5 N solution), and stirred at roomtemperature for 18 hours. The solvent was evaporated and the residue wasdissolved in water (10 mL). Diethyl ether (10 mL) was added and themixture acidified with concentrated HCl. The organic layer wasseparated, and the aqueous phase was extracted with diethyl ether (2×10mL). The combined extracts were dried over MgSO₄, filtered, andevaporated to yield a yellow solid, which was recrystallized in diethylether-hexane to afford the title compound as a yellow solid (0.371 g,80%): mp 154.4–156.4° C. ¹H NMR (acetone-d₆/300 MHz) 7.88 (s, 1H), 7.53(d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.94 (q, 1H, J=7.1 Hz), 3.83(t, 2H, J=6.5 Hz), 2.68 (t, 2H, J=6.8 Hz), 2.12–2.04 (m, 2H). ESLRMS m/z377 (M−H). ESHRMS m/z 376.9930 (M−H, Calc'd. 376.9959). Anal. Calc'd.for C₁₆H₁₁Cl₂F₃O₃+1.18% H₂O: C, 5.0.08; H, 3.02; Cl, 18.48. Found: C,50.11; H, 2.73; Cl, 18.28.

EXAMPLE 119

6-Chloro-8-(1-pentynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 168.1–171.2° C. ¹HNMR (CDCl₃/300 MHz) 7.75 (s, 1H), 7.37 (d, 1H, J=2.6 Hz), 7.15 (d, 1H,J=2.4 Hz), 5.77 (1, 1H, J=6.7 Hz), 2.44 (t, 2H, J=6.9 Hz), 1.68–1.61 (m,2H), 1.07 (t, 3H, J=7.25 Hz. FABLRMS m/z 345 (M+H). ESHRMS m/z 343.0373(M−H, Calc'd. 343.0349). Anal. Calc'd. for C₁₆H₁₂ClF₃O₃+0.69% H₂O: C,55.36; H, 3.56. Found: C, 55.21; H, 3.62.

EXAMPLE 120

6-Chloro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 190.1–192.1° C. ¹HNMR (CDCl₃/300 MHz) 7.92 (s, 1H), 7.61–7.57 (m, 4H), 7.47–7.44 (m, 3H),6.01 (q, 1H, J=7.0 Hz). ESLRMS m/z 377 (M−H). ESHRMS m/z 377.0167 (M−H,Calc'd. 377.0192). Anal. Calc'd. for C₁₉H₁₀ClF₃O₃: C, 60.26; H, 2.66;Cl, 9.36. Found: C, 60.09; H, 2.73; Cl, 9.09.

EXAMPLE 121

6-Chloro-8-(3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 218.3–222.4° C. ¹HNMR (acetone-d₆/300 MHz) 7.87. (s, 1H), 7.51 (d, 1H, J=2.4 Hz), 7.38 (d,1H, J=2.6 Hz), 5.92 (q, 1H, J=6.9 Hz), 1.32 (s, 9H). FABLRMS m/z 359(M+H). ESHRMS m/z 357.0490 (M−H, Calc'd. 357.0505). Anal. Calc'd. forC₁₇H₁₄ClF₃O₃: C, 56.92; H, 3.93; Cl, 9.88. Found: C, 56.63; H, 3.94; Cl,10.03.

EXAMPLE 122

6-Chloro-8-[(4-chlorophenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 210.4–211.4° C. ¹HNMR (CDCl₃/300 MHz) 7.75 (s, 1H), 7.48–7.43 (m, 3H), 7.36 (s, 1H), 7.33(s, 1H), 7.22 (d, 1H, J=2.6 Hz), 5.82 (q, 1H, J=6.6 Hz). FABLRMS m/z 411(M−H). ESHRMS m/z 410.9802 (M−H, Calc'd. 410.980259). Anal. Calc'd. forC₂₀H₁₂C₁₂F₃O₃: C, 55.23; H, 2.20; Cl, 17.16. Found: C, 55.22; H, 2.07;Cl, 17.39.

EXAMPLE 123

6-Chloro-8-[(4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118: mp 217.7–218.7° C. ¹HNMR (CDCl₃/300 MHz) 7.75 (s, 1H), 7.51–7.47 (m, 3H), 7.18 (d, 1H, J=2.4Hz), 6.91–6.88 (m, 2H), 5.82 (1, 1H, J=6.7 Hz). ESLRMS m/z 407 (M−H).ESHRMS m/z 407.0293 (M−H, Calc'd 407.0298). Anal. Calc'd forC₂₀H₁₂ClF₃O₄: C, 58.77; H, 2.96; Cl, 8.67. Found: C, 58.68; H, 2.85; Cl,9.15.

EXAMPLE 124

6-(Phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 240.1–241.3° C. ¹H NMR(acetone-d₆/300 MHz) 7.94 (s, 1H), 7.70–7.69 (m, 1H), 7.61–7.53 (m, 3H),7.44–7.41 (m, 3H), 7.10 (d, 1H, J=7.1 Hz). ESHRMS m/z 343.0550 (M−H,Calc'd. 343.0582). Anal. Calc'd. for C₁₉H₁₁F₃O₃: C, 66.29; H, 3.22.Found: C, 66.26; H, 3.29.

EXAMPLE 125

6-Chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 73, Step 2)(1.3 g, 3.02 mmol), potassium carbonate (1.25 g,9.06 mmol), 4-chorophenylboronic acid (0.52 g, 3.33 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.174 g, 0,151 mmol) wereadded to toluene (30 mL) and the resulting solution was heated to refluxfor 18 hours. After cooling to room temperature the reaction mixture waspoured into ethyl acetate (50 mL). It was washed with 1 N HCl (2×25 mL),saturated aqueous sodium bicarbonate (2×25 mL), and water (2×25 mL). Theorganic phase was dried over MgSO₄, filtered, and concentrated in vacuoto yield a brown oil. The crude material was purified by flashchromatography using 1% ethyl acetate in hexane yielding a white solid.Recrystallization from hexane afforded the ester as a white solid (0.79g, 64%): mp 114.2–115.9° C. ¹H NMR (CDCl₃/300 MHz) 7.69 (s, 1H), 7.41(s, 4H), 7.30 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=2.6 Hz), 5.70 (q, 1H,J=6.9 Hz), 4.37–4.29 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). ESLRMS m/z 434(M+NH₄ ⁺). FABHRMS m/z 434.0574 (M+NH₄ ⁺, Calc'd. 434.0538). Anal.Calc'd. for C₁₉H₁₃Cl₂F₃O₃: C, 54.70; H, 3.14; Cl, 17.00. Found: C,54.79; H, 3.18; Cl, 16.65.

Step 2. Preparation of6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

The ester from Step 1 (0.500 g, 1.20 mmol) was dissolved in a solutionof THF:ethanol:water (7:2:1; 10 mL), treated with sodium hydroxide (0.48mL, 1.20 mmol of a 2.5 N solution), and stirred at room temperature for18 hours. The solvent was removed in vacuo and the residue was dissolvedin water (10 mL). Diethyl ether (10 mL) was added and the mixtureacidified with concentrated HCl. The organic layer was separated, andthe aqueous phase was extracted with diethyl ether (2×10 mL). Thecombined extracts were dried over MgSO₄, filtered, and evaporated toyield a white solid, which was recrystallized in diethyl ether-hexane toafford the title compound as a white solid (0.40 g, 86%): mp205.5–207.3° C. ¹H NMR (CDCl₃/300 MHz) 7.81 (s, 1H), 7.42(s, 4H), 7.34(d, 1H, J=2.4 Hz), 7.25 (s, 1H), 5.69 (q, 1H, J=6.8 Hz). FABLRMS m/z 387(M−H) ESHRMS m/z 386.9788 (M−H, Calc'd. 386.980259). Anal. Calc'd. forC₁₇H₉Cl₂F₃O₃: C, 52.47; H, 2.33; Cl, 18.22. Found: C, 52.38; H, 2.47;Cl, 18.20.

EXAMPLE 126

6-Chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

In a 100 mL round bottomed flask under nitrogen, ethyl6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 73, Step 2) (1.00 g, 2.31 mmol) and 3-methoxyphenylboronic acid(0.369 g, 2.43 mmol) were dissolved in 1-propanol (50 mL). The mixturewas stirred at room temperature for 0.5 hours, allowing for the solidsto dissolve. The resulting solution was treated with palladium (II)acetate (0.016 g, 0.0693 mmol), triphenylphosphine (0.055 g, 0.208mmol), sodium carbonate (0.294 g, 2.77 mmol), and deionized water (10mL). The reaction mixture was heated to reflux for 3 hours. Aftercooling to room temperature the mixture was extracted with ethyl acetate(1×150 mL, 2×25 mL). The combined organic phases were washed withsaturated aqueous NaHCO₃ (50 mL) and brine (2×50 mL), dried over MgSO₄,filtered, and concentrated in vacuo to yield a yellow oil. The crudematerial was purified by flash chromatography in 0.5% ethyl acetate inhexane yielding a white solid. The solid was recrystallized from hexaneyielding the desired ester as a white solid (0.60 g, 63%): mp 93.7–95.1°C. ¹H NMR (CDCl₃/300 MHz) 7.69 (s, 1H), 7.35–7.32 (m, 2H), 7.22 (d, 1H,J=2.6 Hz), 7.05–7.03 (m, 2H), 6.96–6.93 (m, 1H), 5.72 (q, 1H, J=6.7 Hz),4.34–4.31 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). FABLRMS m/z 413 (M+H). ESHRMSm/z 413.0765 (M+H, Calc'd. 413.076747). Anal. Calc'd. for C₂₀H₁₆ClF₃O₄:C, 58.19; H, 3.91; Cl, 8.59. Found: C, 58.33; H, 4.10; Cl, 8.61.

Step 2. Preparation of6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

The ester from Step 1 (0.300 g, 0.727 mmol) was dissolved inTHF-ethanol-water (7:2:1, 10 mL). It was treated with sodium hydroxide(0.29 mL of a 2.5 N solution, 0.727 mmol), and stirred at roomtemperature for 18 hours. The solvent was evaporated and the residue wasdissolved in water (10 mL). Ether (10 mL) was added, followed by a fewdrops of concentrated HCl. The ether layer was separated, and theaqueous phase was extracted with ether (2×10 mL). The ether extractswere combined, dried over MgSO₄, filtered, and concentrated in vacuo toyield a-white solid, which was recrystallized in diethyl ether-hexane toafford the title compound as a white solid (0.23 g, 81%): mp173.1–177.4° C. ¹H NMR (CDCl₃/300 MHz) 7.81 (s, 1H), 7.39–7.37 (m, 2H),7.05–7.04 (m, 2H), 6.97–6.94 (m, 1H), 5.71 (q, 1H, J=6.7 Hz), 3.85 (s,3H). ESHRMS m/z 383.0278 (M−H, Calc'd. 383.029796). Anal. Calc'd. forC₁₈H₁₂ClF₃O₄: C, 56.20; H, 3.14; Cl, 9.21. Found: C, 55.90; H, 3.11; Cl,9.48.

EXAMPLE 127

6-Chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 126: mp 211.4–212.5° C. ¹HNMR (acetone-d₆/300 MHz) 7.94 (s, 1H), 7.57 (d, 1H, J=2.6 Hz), 7.53–7.50(m, 2H), 7.45 (d, 1H, J=2.6 Hz), 7.39–7.36 (m, 2H), 5.87 (q, 1H, J=7.1Hz), 2.55 (s, 3H). ESHRMS m/z 399.0051 (M−H, Calc'd. 399.0069). Anal.Calc'd. for C₁₈H₁₂ClF₃O₃S: C, 53.94; H, 3.02; Cl, 8.84; S, 8.00. Found:C, 53.86; H, 2.82; Cl, 8.91; S, 8.21.

EXAMPLE 128

6-Chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation ofethyl-6-chloro-8[(4-methyl-sulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Oxone™ (1.44 g, 2.34 mmol) was dissolved in H₂O (10 mL) and then chilledto 5° C. A solution of ethyl6-chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 127, ethyl ester) (0.5 g, 1.17 mmol) in methanol (20 mL) wasslowly added to the reaction mixture and the solution was stirred atroom temperature for 5 hours. The methanol was then removed in vacuo.The remaining solution was extracted with methylene chloride (2×50 mL).The combined organic layers were dried over MgSO₄, filtered, andevaporated to yield a yellow solid. This solid was recrystallized inether-hexane to afford the sulfone as a white solid (0.46 g, 84%): mp139.2–146.2° C. ¹H NMR (CDCl₃/300 MHz) 8.03 (s, 1H), 8.00 (s, 1H), 7.70(d, 2H, J=2.4 Hz), 7.28 (d, 1H, J=2.6 Hz), 5.71 (q, 1H, J =6.9 Hz),4.35–4.32 (m, 2H), 3.11(s, 3H), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 467(M+Li). ESHRMS m/z 478.0707 (M+NH₄ ⁺, Calc'd. 478.070281). Anal. Calc'd.for C₂₀H₁₆ClF₃O₅S: C, 52.12; H, 3.50; Cl, 7.69. Found: C, 52.17; H,3.36; Cl, 7.77.

Step 2. Preparation of6-chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.

The sulfone from Step 1 (0.300 g, 0.651 mmol) was dissolved in asolution of THF:ethanol:water (7:2:1; 10 mL). It was treated with sodiumhydroxide (0.26 mL, 0.651 mmol of a 2.5 N solution), and stirred at roomtemperature for 18 hours. The solvent was removed in vacuo and theresidue was dissolved in water (10 mL). Diethyl ether (10 mL) was andthe mixture acidified with concentrated HCl. The organic layer wasseparated, and the aqueous phase was extracted with diethyl ether (2×10mL). The combined organic extracts were dried over MgSO₄, filtered, andevaporated to yield a white solid. Recrystallization of this solid inether-hexane afforded the title compound as a white solid (0.20 g, 73%):mp 286.5–287.8° C. ¹H NMR (acetone-d₆/300 MHz) 8.07 (d, 2H, J=6.7 Hz),7.97 (s, 1H), 7.84 (d, 2H, J=6.7 Hz), 7.67 (d, 1H, J=2.6 Hz), 7.55 (d,1H, J=2.6 Hz), 5.92 (q, 1H, J=7.1 Hz), 3.20 (s, 1H). ESHRMS m/z 430.9947(M−H, Calc'd. 430.996782). Anal. Calc'd. for C₁₈H₁₂ClF₃O₅S: C, 49.95; H,2.80; Cl, 8.19. Found: C, 50.04; H, 2.80; Cl, 8.25.

EXAMPLE 129

6-Chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl6-chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A mixture of ethyl6-chloro-8-bromo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 74, Step 1) (2.0 g, 5.2 mmol),tetrakis(triphenylphosphine)palladium (0) (2.15 g, 1.7 mmol),triphenylphosphine (0.013 g, 0.05 mmol), and tributylphenyltin (1.9 mL,5.7 mmol) in toluene (60 mL) was heated to 110° C. for 3 days. Thereaction mixture was allowed to cool to room temperature and filteredthrough a plug of silica gel eluting with 25% ethyl acetate in hexanes.The filtrate was concentrated in vacuo and then purified by flashchromatography (silica gel, ethyl acetate-hexanes, 1:9). The fractionscontaining desired, product were combined and concentrated in vacuo. Toremove the remaining tin impurities the mixture was taken up in THF (10mL) and aqueous ammonium fluoride solution (10 wt %, 20 mL) and stirredat room temperature for 2 hours. The solution was extracted with ethylacetate. The extracts were combined, dried over MgSO₄, filtered, andconcentrated in vacuo to afford the ester as an oil (1.30 g, 65%). ¹HNMR (CDCl₃/300 MHz) 7.67 (s, 1H), 7.47–7.36 (m, 5H), 7.31 (d, 1H, J=2.6Hz), 7.18 (d, 1H, J=2.4 Hz), 5.69 (q, 1H, J=6.8 Hz), 4.30 (m, 2H), 1.33(t, 3H, J=7.1 Hz). ¹⁹FNMR (CDCl₃/282 MHz) d −78.27 (d, J=7.2 Hz).FABLRMS m/z 383 (M+H). ESHRMS m/z 400.0937 (M+NH₄, Calc'd 400.0927)

Step 2. Preparation of6-chloro-8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

A solution of the ester from step 1 (1.0 g, 2.6 mmol) was dissolved inTHF (5 mL) and methanol (5 mL) was treated with a 2.5 N NaOH solution(4.0 mL, 10.4 mmol). The resulting mixture was stirred at roomtemperature for 18 hours. The solvent was removed in vacuo, and theresidue taken up in ethyl acetate and acidified with 3 N HCl. Thesolution was extracted with ethyl acetate. The extracts were combined,dried over MgSO₄, filtered, and concentrated in vacuo yielding a yellowsolid. Recrystallization from ethyl acetate-hexanes afforded the titlecompound as a pale yellow solid (0.42 g, 46%): mp 196.3–197.7° C. ¹H NMR(CDCl₃/300 MHz) d 7.65 (s, 1H), 7.40–7.23 (m, 6H), 7.15 (s, 1H), 5.63(q, 1H, J=6.5 Hz), 3.35 (broad s, 1H). ¹⁹F NMR (CDCl₃/282 MHz) d −78.71(d, J=5.8 Hz). FABLRMS m/z 355 (M+H). ESHRMS m/z 353.0198 (M−H, Calc'd353.0192).

EXAMPLE 130

6-Bromo-8-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

4-Bromo-2-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 206–208° C. ¹H NMR(CD₃OD/300 MHz) 7.78 (s, 1H), 7.36–7.48 (m, 2H), 5.87 (q, 1H, J=6.8 Hz).EIHRMS m/z 339.9349 (Calc'd 339.9358). Anal. Calc'd for C₁₁H₅BrF₄O₃: C38.74, H 1.48; Found C 38.97, H, 1.60.

EXAMPLE 131

6-(4-Fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 207–210° C. ¹H NMR (CD₃OD/300 MHz)7.87 (s, 1H), 7.54–7.64 (m, 4H), 7.10–7.20 (m, 2H), 7.03 (d, 1H, J=9.4Hz), 5.77 (q, 1H, J=7.0 Hz). EIHRMS m/z 338.0573 (Calc'd 338.0566) Anal.Calc'd for C₁₁H₆F₃IO₃+1.25% H₂O: C, 59.62; H, 3.08. Found C, 59.61; H,3.09.

EXAMPLE 132

6-Phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 197–198° C. ¹H NMR (CD₃OD/300 MHz)7.87 (s, 1H); 7.28–7.64 (m, 7H), 7.03 (d, 1H, J=6.8 Hz), 5.76 (q, 1H,J=7.0 Hz). EIHRMS m/z 320.0604 (M+, Calc'd 320.0660). Anal. Calc'd forC₁₇H₁₁F₃O₃: C, 63.75; H 3.46. Found C, 63.56; H, 3.46.

EXAMPLE 133

8-Chloro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

2-Chloro-4-fluorophenol was converted to the title compound by aprocedure similar to that described in Example 2: mp 240–241° C. ¹H NMR(CD₃OD/300 MHz) 7.77 (s, 1H), 7.26 (dd, 1H, J=8.3, 2.9), 7.14 (dd, 1H,J=8.1, 2.9), 5.87 (q, 1H, J=6.8 Hz). EIHRMS m/z 295.9836 (Calc'd295.9863). Anal. Calc'd for C₁₁H₅ClF₄O₃: C, 44.54; H, 1.70. Found C,44.70; H, 1.73.

EXAMPLE 134

6,8-Diiodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 1: mp 243–244° C. ¹H NMR(CD₃OD/300 MHz) 8.07 (d, 1H, J=2.0 Hz), 7.71 (s, 1H), 7.70 (d, 1H, J=2.0Hz), 5.89 (q, 1H, J=6.8 Hz). ESHRMS m/z 494.8174 (Calc'd for M−H494.8202) Anal. Calc'd for C₁₁H₅F₃I₂O₃: C, 26.64; H, 1.02. Found C,26.75; H, 1.06.

EXAMPLE 135

6-(5-Chloro-2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 72,Step 3) as the starting material: mp 205–206° C. ¹H NMR (CD₃OD/300 MHz)7.83 (s, 1H), 7.50–7.58 (m, 2H), 7.14 (d, 1H, J=4.0 Hz), 7.00 (d, 1H,J=8.86 Hz), 6.93 (d, 1H, J=4.0 Hz), 5.77 (q, 1H, J=7.0 Hz). EIHRMS m/z359.9810 (M+, Calc'd 359.9835). Anal. Calc'd for C₁₅H₈ClF₃O₃S: C, 49.94;H 2.24. Found C, 50.14; H, 2.29.

EXAMPLE 136

6-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 209–212° C. ¹H NMR (CD₃OD/300 MHz)7.83 (s, 1H), 7.58–7.62 (m, 2H), 7.30–7.38 (m, 2H), 6.80–7.09 (m, 2H),5,76 (q, 1H, J=7.0 Hz) FABHRMS m/z 325.0153 (Calc'd for M−H 325.0146)

EXAMPLE 137

6-(4-Chlorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 125 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 212–213° C. ¹H NMR (CD₃OD/300 MHz)7.89 (s, 1H); 7.56–7.66 (m, 4H), 7.40–7.48 (m, 2H), 7.04–7.10 (m, 1H),5.77 (q, 1H, J=7.0 Hz). ESHRMS m/z 353.0190 (Calc'd for M−H 353.0192).Anal. Calc'd for C₁₇H₁₀ClF₃O₃: C, 57.56; H, 2.84. Found C, 57.41; H,2.82.

EXAMPLE 138

6-(4-Bromophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 126: using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 215–216° C. ¹H NMR (CD₃OD/300 MHz)7.89 (s, 1H), 7.06–7.71 (m, 6H), 7.04–7.06 (m, 1H), 5.78 (q, 1H, J=6.8Hz). ESHRMS m/z 396.9681 (Calc'd for M−H 396.9687).

EXAMPLE 139

6-(Ethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 118 using ethyl6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 24,Step 3) as the starting material: mp 198–200° C. ¹H NMR (CD₃OD/300 MHz)7.80 (s, 1H), 7.47 (dd, 1H, J=8.5, 2.0 Hz), 7.41 (d, 1H, J=2.0 Hz), 6.97(d, 1H, J=8.5 Hz), 5.71 (q, 1H, J=6.8 Hz), 3.06 (s, 1H). ESHRMS m/z267.0271 (Calc'd for M−H 267.0269) Anal. Calc'd for C₁₃H₇F₃O₃+1.06% H₂O:C, 57.60; H, 2.72. Found C, 57.59; H, 2.62.

EXAMPLE 140

6-Methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

4-Methylsalicylaldehyde was converted to the title compound by aprocedure similar to that described in Example 1: mp 191.8–193.0° C. ¹HNMR (acetone-d₆/300 MHz) 7.80 (s, 1H), 7.72–7.73 (m, 2H), 6.90 (d, 1H,J=8.4 Hz), 5.91 (q, 1H, J=7.2 Hz). Anal. Calc'd for C₁₂H₉O₃F₃: C, 55.82;H, 3.51. Found: C, 55.89; H, 3.49.

EXAMPLE 141

6-Chloro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 126: mp 194.0–196.0° C. ¹HNMR (CDCl₃/300 MHz) 7.81 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.34 (d,1H, J=2.4 Hz),7.21 (d, 1H, J=2.4 Hz), 6.99 (s, 1H), 6.96 (s, 1H), 5.69(q, 1H, J=6.7 Hz), 3.86 (s, 3H). FABLRMS m/z 402.2 (M+NH₄). ESHRMS m/z383.0267 (M−H, Calc'd. 383.029796). Anal. Calc'd. for C₁₈H₁₂ClF₃O₄: C,56.20; H, 3.14; Cl, 9.21. Found: C, 56.08; H, 3.11; Cl, 9.13.

EXAMPLE 142

6-Chloro-2-(trifluoromethyl)-4-ethenyl-2H-1-benzopyran-3-carboxylic acid

Step 1: Preparation of ethyl3-(5-chloro-2-hydroxyphenyl)-3-oxo-propionate

A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution inTHF, 800.0 mmol) was chilled to −78° C. under a nitrogen atmosphere. Asolution of 5-chloro-2-hydroxyacetophenone (45.493 g, 266.67 mmol) inTHF (130 mL) was added dropwise to the stirred solution over 0.5 hour.The reaction was held at −78° C. for 1 hour, warmed to −10° C. for 2hours, warmed to 0° C. for 1 hour, then cooled to −78° C. Diethylcarbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringe in oneportion. The temperature was maintained at −78° C. for 0.5 hour, warmedto room temperature over 0.5 hour, and stirred for 3 hours. The crudereaction mixture was carefully poured over a mixture of rapidly stirredice (1200 mL)/conc HCl (222 mL). The layers were separated and theaqueous phase was extracted with ethyl acetate. The combined organicphase was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo yielding an oil that began to crystallize. Hexanes(150 mL) was added and crystallization proceeded. The crystallineproduct was collected by vacuum filtration to afford the title compound(29.04 g, 45%) as tan crystalline needles: mp 71.8–73.1° C. ¹H NMR(CDCl₃/300 MHz) 7.63 (d, 1H, J=2.4 Hz), 7.45. (dd, 1H, J=8.9, 2.6), 6.98(d, 1H, J=8.9 Hz), 4.25 (q, 2H, J=7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H,7.3 Hz). FABLRMS m/z 249 (M+Li). EIHRMS m/z 242.0346 (M+, Calc'd242.0346). Anal. Calc'd for C₁₁H₁₁ClO₄: C, 54.45; H, 4.57. Found: C,54.48; H, 4.62.

Step 2. Preparation of ethyl2-(trifluoromethyl)-6-chloro-4-oxo-4H-1-benzopyran-3-carboxylate.

The keto-ester (Step 1) (19.2 g, 79.1 mmol), was added totrifluoroacetic anhydride (67.2 mL, 49.9 g, 475.8 mmol), potassiumcarbonate (44 g, 318 mmol) and toluene (400 mL). This suspension wasstirred at room temperature for 36 hours, then heated to reflux for 4hours. After cooling to room temperature, the suspension was poured overrapidly stirred (mechanical stirrer) ice (300 mL) and aqueous HCl (12 N,50 mL). The resulting organic phase was separated from the clearmixture, was washed with water (5×500 mL), brine (1×500 mL), dried overMgSO₄, filtered and concentrated in vacuo yielding tan solid which wasdried under high vacuum. This sample was partially dissolved in heptane(100 mL) and ethyl acetate (12 mL) with heating on a steam bath, wasfiltered to remove insoluble material. The filtrate was allowed to coolto room temperature yielding the desired 4-oxo-4H-1-benzopyran as afluffy tan solid (14.17 g, 56%): mp 106.7–108.6° C. This material was ofsuitable purity to use in the next step without further purification.

Step 3. Preparation of ethyl2-(trifluoromethyl)-4-oxo-dihydro-1-benzopyran-3-carboxylate.

A stirred, chilled (0° C.) solution of the ketone (Step 2) (6.92 g,21.58 mmol) in tetrahydrofuran (40 mL) and ethanol (50 mL) was treatedportion-wise with sodium borohydride (NaBH₄, 0.41 g, 10.79 mmol). After3 h additional sodium borohydride (0.30 g, 7.93 mmol) was addedportion-wise over 1 hour. The reaction was poured into rapidly stirredcold aqueous HCl (15 mL of 12 N HCl diluted to 300 mL). During theaddition a precipitate formed, that was collected by vacuum filtrationand dried under high vacuum yielding the desired substituted4-oxo-dihydro-1-benzopyran as a white powder (6.92 g, 99%): mp80.2–84.9° C. ¹H NMR (CDCl₃/300 MHz) 12.60 (br s, 1H), 7.69 (d, 1H,J=2.6 Hz), 7.34 (dd, 1H, J=2,6, 8.7 Hz), 6.93 (d, 1H, J=8.7 Hz), 5.59(q, 1H, 6.6 Hz), 4.46–4.23 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z329 (M+Li). EIHRMS m/z 322.0213 (M+, Calc'd 322.0220). Anal. Calc'd forCl₃H₁₀Cl₁F₃O₄ with 3.57% water: C, 46.67; H, 3.41. Found: C, 46.62; H,3.14.

Step 4. Preparation of ethyl6-chloro-4-(trifluoromethanesulfonoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A 50 mL Morton flask fitted with septa and addition funnel was chargedwith 2,6-di-tert-butylpyridine (1.782 g, 8.679 mmol), methylene chloride(15 mL), and trifluoromethanesulfonic anhydride (1.22 mL, 2.04 g, 7.23mmol) followed by the dropwise addition of the chroman-4-one (Step 3)(2.145 g, 5.786 mmol) in methylene chloride (12 mL) over 0.33 hour.After stirring for 16 h at room temperature, the reaction wasconcentrated in vacuo and diluted with diethyl ether (50 mL) yielding asuspension. The suspension was vacuum filtered and the filtrate washedwith cold 2 N HCl and brine, dried over MgSO4, filtered and concentratedin vacuo yielding the desired triflate as a light yellow powder (1.45 g,55%) of suitable purity to use without further purification: mp79.2–80.4° C. ¹H NMR (CDCl₃/300 MHz) 7.40 9s, 1H), 7.37 (d, 1H, J=2.4Hz), 7.02–6.99 (m, 1H), 5.92 (q, 1H, J=6.6 Hz), 4.47–4.32 (m, 2H), 1.39(t, 3H, J=7.2 Hz).

Step 5. Preparation of ethyl6-chloro-4-ethenyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

Ethyl6-chloro-4-trifluoromethanesulfoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Step 4) (1.50 g, 3.30 mmol) was dissolved in anhydrous THF (40 mL) in a100 mL round bottomed flask under-nitrogen.Tetrakis(triphenylphosphine)palladium(0) (0.267 g, 0.231 mmol) andlithium chloride (0.140 g, 3.3 mmol) were added, followed bytributylethenylstannane (1.15 g, 3.6 mmol). The resulting solution washeated to reflux for 18 hours. GCMS analysis indicated the startingmaterial had been consumed. The reaction mixture was allowed to cool toroom temperature and was poured into 20% ammonium fluoride solution (50mL). After stirring for one hour, diethyl ether (100 mL) was added andthe mixture was washed with water (2×50 mL). The organic phase was driedover MgSO₄, filtered, and concentrated in vacuo yielding a brown oil.The crude material was purified by flash column chromatography (hexane)to afford the ester as a yellow oil, which crystallized upon standing(0.760 g, 69%): mp 51.9–53.2° C. ¹H NMR (CDCl₃/300 MHz) 7.46 (d, 1H,J=2.4 Hz), 7.28–7.14 (m, 2H), 6.96 (d, 1H, J=8.7 Hz), 5.77–5.71 (m, 2H),5.38 (dd, J=1.2, 17.9 Hz), 4.32–4.26 (m, 2H), 1.33 (t, 2H, J=7.1 Hz).FABLRMS m/z 333.2 (M+H). ESHRMS m/z 333.0510 (M+H, Calc'd. 333.050532.Anal. Calc'd for C₁₅H₁₂ClF₃O₃ (1.14 wt % H₂O): C, 53.53; H, 3.72; Cl,10.53. Found: C, 53.46; H, 3.42; Cl, 10.70.

Step 6. Preparation of6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid.

The ester from Step 5 (0.300 g, 0.902 mmol) was dissolved in aTHF-EtOH-H₂O mixture (10 mL, 7:2:1) and treated with sodium hydroxide(0.360 mL, 0.902 mmol of a 2.5 N solution). This solution was stirred atroom temperature for 18 hours. The solvent was evaporated and theresidue was dissolved in water (10 mL). Diethyl ether (10 mL ) was addedand the mixture acidified by the addition of concentrated HCl. Theorganic layer was separated, and the aqueous phase was extracted withdiethyl ether (2×10 mL). The ether extracts were combined, dried overMgSO₄, filtered, and concentrated in vacuo yielding a yellow solid,which was recrystallized in diethyl ether-hexane to afford the titlecompound as a white solid (0.163 g, 59%): mp 143.0–145.0° C. 1H NMR(CDCl₃/300 MHz 7.49 (d, 1H, J=2.6 Hz), 7.33–7.17 (m, 2H), 6.99 (d, 1H,J=8.5 Hz), 5.82–5.72 (m, 2H), 5.42 (d, 1H, J=17.9 Hz). ESHRMS m/z303.00207 (M−H, Calc'd. 303.003582). Anal. Calc'd for C₁₃H₈ClF₃O₃ (1.10wt % H₂O): C, 50.69; H, 2.74; Cl, 11.51. Found: C, 50.57; H, 2.37; Cl,11.75.

EXAMPLE 143

6-Chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared from ethyl6-chloro-4-(trifluoromethanesulfonoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 142, Step 4) using a procedure similar to that described inExample 142, Steps 5–6: mp 225.5–226.6° C. 1H NMR (DMSO-_(d6)/300 MHz).7.46–7.39 (m, 4H), 7.20–7.13 (m, 3H), 6.52 (d, 1H, J=2.42 Hz), 6.12 (q,1H, J=7.1 Hz). FABLRMS m/z 355.1 (M+H). ESHRMS m/z 353.0215 (M−H,Calc'd. 353.019232). Anal. Calc'd. for C₁₇H₁₀ClF₃O₃: C. 57.56; H, 2.84;Cl, 10.17. Found: C, 57.18; H, 2.66; Cl, 10.17.

EXAMPLE 144

6-Chloro-4-(2-thienyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

The 2H-1-benzopyran-3-carboxylic acid was prepared from ethyl6-chloro-4-(trifluoromethanesulfonoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate(Example 142, Step 4) using a procedure similar to that described inExample 142, Steps 5–6: mp 200.8–206.7° C. ¹H NMR (CDCl₃/300 MHz) 7.52(dd, 1H, J=1.21, 5.04 Hz), 7.28 (dd, 1H, J=2.42, 8.67 Hz), 7.15 (dd, 1H,J=1.21, 3.42 Hz), 6.98–6.93 (m, 2H), 5.83 (q, 1H, J=6.9 Hz). FABLRMS m/z378 (M+NH₄). Anal. Calc'd. for C₁₅H₈ClF₃O₃S: C, 49.94; H, 2.24; Cl,9.83; S. 8.89. Found: C, 50.02; H, 1.98; Cl, 9.34; S, 8.89.

EXAMPLE 145

6-Methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

Step 1. Preparation of 5-methyl-2-mercaptobenzaldehyde.

Tetramethylethylenediamine (TMEDA) (12.6 mL, 83.5 mmol) was added viasyringe to n-BuLi (33 mL of 1.6 M in hexanes, 82.5 mmol) and thesolution was chilled to 0° C. A solution of p-thiocresol (4.53 g, 36.5mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. Theresulting tan slurry was stirred overnight at room temperature, chilledto 0° C., and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over2 minutes. The resulting gummy slurry was stirred at room temperaturefor 1.3 hours. The reaction mixture was added to 3 N HCl (150 mL). Thismixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentrated invacuo yielding a brown oil. This oil was purified by flashchromatography over silica gel, eluting with 10% ethyl acetate-hexanesto afford 5-methyl-2-mercaptobenzaldehyde (4.47 g, 69%) as an intenselyyellow solid suitable for use without further purification.

Step 2. Preparation of ethyl6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate.

The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g, 21.3 mmol) wasadded to DMF (5 mL) and ethyl 4,4,4-trifluorocrotonate (4.32 g, 25.7mmol). With stirring, K₂CO₃ (3.78 g, 27.3 mmol) was added causing thereaction to become a deep red. The reaction was stirred at roomtemperature for 20 hours, acidified with 3N HCl, diluted with ethylacetate and washed with water, saturated NaHCO₃ solution, brine, driedover MgSO₄, filtered and concentrated in vacuo yielding an oil. The oilwas crystallized from diethyl ether-petroleum ether to give ethyl6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate as alight yellow solid (4.47 g, 69%),: mp 93.1–94.7° C. ¹H NMR(acetone-d6/300 MHz) 7.94 (s, 1H), 7.41 (s, 1H), 7.31 (d, 1H, J=7.9 Hz),7.25 (d, 1H, J=7.9 Hz), 4.96 (q, 1H, J=8.5 Hz), 4.33 (m, 2H), 2.34 (s,3H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 309 (M+Li).

Step 3. Preparation of6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid.

The ester from Step 2 (0.55 g 1.8 mmol) was dissolved in THF (1.5 mL)and ethanol (1.5 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8mmol), and stirred at room temperature for 88 hours. The reactionmixture was concentrated in vacuo, acidified with 3 N HCl, filtered, andrecrystallized from diethyl ether/petroleum ether to yield the titlecompound as a yellow solid (0.14 g, 28%): mp 180.8–184.2° C. ¹H NMR(acetone-d6/300 MHz) 7.95 (s, 1H), 7.42 (s, 1H), 7.31 (d, 1H, J=8.1 Hz),7.25 (d, 1H, J=8.1 Hz), 4.94 (q, 1H, J=8.7 Hz), 2.34 (s, 3H). FABLRMSm/z 281 (M+Li). EIHRMS m/z 274.0250 (M+, Calc'd 274.0275). Anal. Calc'dfor C₁₂H₉F₃O₂S: C, 52.55; H, 3.31. Found: C, 52.54; H, 3.35.

EXAMPLE 146

6,8-Dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 145: mp 220–225° C. (dec). ¹HNMR (acetone-d6/300 MHz) 11.5 (brs, 1H), 7.94 (s, 1H), 7.26 (s, 1H) 7.14(s, 1H), 4.98 (q, 1H, J=8.7 Hz), 2.34 (s, 3H), 2.31 (s, 3H). FABLRMS m/z295 (M+Li). EIHRMS m/z 288.0431 (M+, Calc'd 288.0432). Anal. Calc'd forC₁₃H₁₁F₃O₂S: C, 54.16; H, 3.85. Found: C, 54.10; H, 3.91.

EXAMPLE 147

6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 145: mp 183.8–184.6° C. ¹HNMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.68 (d, 1H, J=2.2 Hz), 7.46 (dd,1H, J=8.3 Hz 2.2 Hz), 7.37 (d, 1H, J=8.3 Hz), 4.94 (q, 1H, J=8.7 Hz),1.34 (s, 9H). FABLRMS m/z 334 (M+NH₄). ESHRMS m/z 334.1087 300 MHz) 7.52(dd, 1H, J=1.21, 5.04 Hz), 7.28 (dd, 1H, J=2.42, 8.67 Hz), 7.15 (dd, 1H,J=1.21, 3.42 Hz), 6.98–6.93 (m, 2H), 5.83 (q, 1H, J=6.9 Hz). FABLRMS m/z378 (M+NH₄). Anal. Calc'd. for C₁₅H₈ClF₃O₃S: C, 49.94; H, 2.24; Cl,9.83; S, 8.89. Found: C, 50.02; H, 1.98; Cl, 9.34; S, 8.89.(M+NH₄,Calc'd 334.1089). Anal. Calc'd for C₁₅H₁₅F₃O₂S: C, 56.95; H, 4.78.Found: C, 57.03; H, 4.83.

EXAMPLE 148

7-Methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 145: mp 186.6–191.9° C. ¹HNMR (acetone-d6/300 MHz) 7.96 (s, 1H), 7.49 (dd, 1H, J=7.6 Hz 2.82 Hz),7.27 (s, 1H), 7.14 (d, 1H, J=7.6 Hz), 4.96 (q, 1H, J=5.3 Hz), 2.36 (s,3H). ESHRMS m/z 273.0204 (M−H, Calc'd 273.0197). Anal. Calc'd forC₁₂H₉F₃O₂S (3.32 wt % H₂O): C, 50.81; H, 3.57. Found: C, 50.79; H, 3.44.

EXAMPLE 149

6,7-Dimethyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 145: mp 235–237° C. ¹H NMR(acetone-d6/300 MHz). 7.90 (s, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 4.91 (q,1H, J=8.7 Hz), 2.28 (s, 3H), 2.26 (s, 3H). FABLRMS m/z 295 (M+Li).EIHRMS m/z 288.0439 (M+, Calc'd 288.0432). Anal. Calc'd for C₁₃H₁₁F₃O₂S:C, 54.16; H, 3.85. Found: C, 54.13; H, 3.85.

EXAMPLE 150

8-Methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 145: mp 224–225° C. ¹H NMR(acetone-d6/300 MHz) 11.60 (br s, 1H), 8.00 (s, 1H), 7.44 (d, 1H, J=6.7Hz), 7.31 (d, 1H, J=6.8 Hz), 7.21 (m, 1H), 5.05 (q, 1H, J=8.5 Hz), 2.38(s, 3H). FABLRMS m/z 292 (M+NH₄). ESHRMS m/z 292.0591 (M+NH₄, Calc'd292.0619). Anal. Calc'd for C₁₂H₉F₃O₂S: C, 52.55; H, 3.31. Found: C,52.63; H, 3.38.

EXAMPLE 151

2-(Trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 145: mp 187–190° C. ¹H NMR(acetone-d6/300 MHz) 8.01 (s, 1H), 7.60 (d, 1H, J=7.5 Hz), 7.45 (m, 2H),7.31 (m, 1H), 4.98 (q, 1H, J=8.7 Hz). ESHRMS m/z 259.0070 (M−H, Calc'd259.0041). Anal. Calc'd for C₁₁H₇F₃O₂S: C, 50.77; H, 2.71. Found: C,50.75; H, 2.78.

EXAMPLE 152

6-Chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

Step 1. Preparation ofN,N-dimethyl-O-(4-chloro-2-formyl-5-methylphenyl)thiocarbamate.

A mixture of 5-chloro-4-methylsalicylaldehyde (12.96 g, 76.0 mmol) andtriethylamine (11.58 g, 114.4 mmol) was dissolved in anhydrous DMF (15mL) treated with N,N-dimethylthiocarbamoyl chloride (11.25 g, 91.0 mmol)and stirred at room temperature for 16 hours. The reaction was treatedwith 3 N HCl (50 mL) and filtered to give an orange solid. The solid wasdissolved in ethyl acetate washed with 3 N HCl water, brine, dried overanhydrous MgSO4, filtered and concentrated in vacuo to afford a brownsolid (16.79 g) which was recrystallized from diethyl ether/hexane togive the O-aryl thiocarbamate as a tan solid (4.92 g, 25%): ¹H NMR(acetone-d6/300 MHz) 9.96 (s, 1H), 7.80 (s, 1H), 7.19 (s, 1H), 3.46 (s,3H), 3.42 (s, 3H), 2.43 (s, 3H).

Step 2. Preparation ofN,N-dimethyl-S-(4-chloro-2-formyl-5-methylphenyl)thiocarbamate.

The O-aryl thiocarbamate (Step 1) (4.92 g, 19.1 mmol) was dissolved inN,N-dimethylaniline (25 mL) and immersed in and stirred at 200° C. for1.5 hours. The reaction mixture was cooled to room temperature andpoured into a mixture of 3 N HCl (200 mL) and ice. Filtration gave abrown semisolid which was dissolved in ethyl acetate, washed with 3 NHCl, brine, dried over anhydrous MgSO4, filtered and concentrated invacuo to afford the S-arylthiocarbamate as a brown oil (3.80 g, 77%)which was used in the next step without further purification.

Step 3. Preparation of ethyl6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate.

The S-arylthiocarbamate (Step 2) (3.80 g, 14.7 mmol) was dissolved inTHF (10 mL) and ethanol (10 mL), treated with 2.5 N sodium hydroxide(16.5 mL, 34.2 mmol), and stirred at room temperature for 0.9 hours. Thereaction was diluted with diethyl ether and washed with 3 N HCl brine,dried over MgSO₄, filtered and concentrated in vacuo to yield the crudesubstituted 2-mercaptobenzaldehyde as a brown oil (2.82 g). This oil wasadded to DMF (10 mL) and ethyl 4,4,4-trifluorocrotonate (3.89 g, 23.1mmol). With stirring, K₂CO₃ (3.23 g, 23.4 mmol) was added causing thereaction to become a deep red. The reaction was stirred at roomtemperature for 14.5 hours, acidified with 3 N HCl, extracted with ethylacetate. The resulting organic phase was washed with brine, dried overMgSO₄, filtered and concentrated in vacuo to give a yellow solid (6.36g) which was used in the next step without further purification.

Step 4. Preparation of6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylicacid

The ester from Step 3 (2.02 g, 6.0 mmol) was dissolved in THF (10 mL)and ethanol (10 mL), treated with 2.5 N sodium hydroxide (5.5 mL, 13.8mmol), and stirred at room temperature for 4.8 hours. The reactionmixture was concentrated in vacuo, acidified with 3 N HCl yielding asuspension. The solid was collected by filtration and was recrystallizedfrom ethanol-water to yield the title compound as a yellow solid (0.20g, 11%): mp 240.5–241.7° C. ¹H NMR (acetone-d6/300MHz) 7.99 (s, 1H),7.67 (s, 1H), 7.43 (s, 1H), 4.99 (q, 1H, J=8.5 Hz), 2.39 (s, 3H).FABLRMS m/z 307 (M−H). FABHRMS m/z 306.9831 (M−H, Calc'd 306.9807).Anal. Calc'd for C₁₂H₈ClF₃O₂S: C, 46.69; H, 2.61; Cl, 11.48. Found: C,46.78; H, 2.61; Cl, 11.41.

EXAMPLE 153

7-Chloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 152: mp 225.7–227.3° C. ¹HNMR (acetone-d6/300 MHz) 8.02 (s, 1H), 7.63 (d, 1H, J=8.3 Hz), 7.54 (d,1H, J=2.0 Hz), 7.36 (dd, 1H, J=8.3 Hz 2.0 Hz), 5.04 (q, 1H, J=8.5 Hz).ESHRMS m/z 292.9646 (M−H, Calc'd 292.9651).

EXAMPLE 154

6,7-Dichloro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 152: mp 262.5–263.5° C. ¹HNMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 5.09(q, 1H, J=8.5 Hz). ESHRMS m/z 326.9242 (M−H, Calc'd 326.9261).

EXAMPLE 155

2-(Trifluoromethyl)-6-[(trifluoromethyl)thiol-2H-1-benzothiopyran-3-carboxylicacid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 152: mp 129.3–132.4° C. ¹HNMR (acetone-d6/300 MHz) 8.10 (s, 2H), 8.00 (s, 2H), 7.71 (d, 2H, J=8.1Hz), 7.65 (d, 2H, J=8.1 Hz), 5.09 (q, 1H, J=8.5 Hz). ESHRMS m/z 358.9630(M−H, Calc'd 358.9635).

EXAMPLE 156

6,8-Dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid

The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a proceduresimilar to the method described in Example 152: mp 217.9–220.3° C. ¹HNMR (acetone-d₆/300 MHz) 12.50–11.20 (br s, 1H exch.), 8.06 (s, 1H),7.75 (d, 1H, J=2.0 Hz), 7.64 (d, 1H, J=2.2 Hz), 5.23 (q, 1H, J=8.5 Hz).ESLRMS m/z 327 (M−H). ESHRMS m/z 326.9272 (M−H, Calc'd 326.9261).

EXAMPLE 157

6-Chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

Step 1. Preparation of 2-amino-5-chlorobenzaldehyde.

2-Amino-5-chlorobenzyl alcohol (4.8 g, 30 mmol) and activated manganese(IV) oxide (21 g, 240 mmol) were refluxed in chloroform (100 mL) for 1hour. The contents were allowed to cool, filtered through diatomaceousearth and concentrated in vacuo to afford the2-amino-5-chlorobenzaldehyde as a dark solid (4.14 g, 81%): mp 74–76° C.¹H NMR (CDCl₃, 300 MHz) 9.80 (s, 1H), 7.42 (s, 1H), 7.23 (d, 1H, J=7.0Hz), 6.60 (d, 1H, J=7.0 Hz).

Step 2. Preparation of ethyl6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol),anhydrous potassium carbonate (27.6 g, 200 mmol), and ethyl4,4,4-trifluorocrotonate (34 mL, 200 mmol) were mixed in anhydrousdimethyformamide (60 mL) and heated at 100° C. for 7 hours. The contentswere allowed to cool and partitioned between ethyl acetate (200 mL) andwater (200 mL). The aqueous layer was extracted with ethyl acetate(1×100 mL). The ethyl acetate extracts were combined and washed withbrine (1×200 mL), dried over MgSO₄, and concentrated in vacuo leaving adark oil which solidified upon standing. The solid was purified by flashchromatography (silica gel; ethyl acetate-hexanes, 1:9). Fractionscontaining the desired product were combined, concentrated in vacuo andthe residue recrystallized from ethyl acetate-hexanes to afford theethyl 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate asa yellow solid (16.36 g, 56%): mp 132.6–134.2° C. ¹H NMR (CDCl₃, 300MHz) 7.61 (s, 1H), 7.10 (m, 2H), 6.55 (d, 1H, J=8.0 Hz), 5.10 (q, 1H,J=6.0 Hz), 4.55 (brs, 1H), 4.23 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). FABHRMSm/z 306.0468 (M+H⁺, Calc'd 306.0509). Anal. Calc'd for C₁₃H₁₁NO₂F₃Cl: C,51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72.

Step 3. Preparation of6-chloro-1,2-dihydro-2-(trifluoro-methyl)-3-quinolinecarboxylic acid.

The ester from Step 2 (1.7 g, 5.6 mmol) and 2.5 N sodium hydroxide (4.4mL, 11 mmol) were mixed in tetrahydrofuran (25 mL), methanol (10 mL),and water (25 mL). After stirring overnight, contents were concentratedin vacuo to remove the THF and methanol. The aqueous solution remainingwas extracted with diethyl ether (2×100 mL). The resulting aqueous layerwas acidified with 2 N HCl causing the precipitation of an oil. The oilwas purified by flash chromatography on silica gel, eluting with ethylacetate-hexanes (1:1). Fractions containing the desired product werecombined, and concentrated in vacuo. The residue was triturated withdichloromethane, and filtered to afford the6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid as ayellow solid (0.645 g, 41%): mp 187.8–188.8° C. ¹H NMR (acetone-d₆, 300MHz) 7.69 (s, 1H), 7.36 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 6.83 (d, 1H,J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). ESHRMS m/z 276.0040 (M−H,Calc'd 276.0039). Anal. Calc'd for C₁₁H₇NO₂F₃Cl+2.6% H₂O: C, 46.39; H,2.98; N, 4.92. Found: C, 45.99; H, 2.54; N, 4.85.

EXAMPLE 158

6,8-Dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 157: mp 223.4–225.7° C. ¹H NMR(acetone-d₆, 300 MHz) 7.82 (s, 1H), 7.40 (m, 2H), 6.53 (brs, 1H), 5.40(m, 1H). ESHRMS m/z 309.9657 (M−H, Calc'd 309.9649). Anal. Calc'd forC₁₁H₆NO₂F₃Cl₂: C, 42.34; H, 1.94; N, 4.49. Found: C, 42.20; H, 1.74; N,4.52.

EXAMPLE 159

6,7-Difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 157: mp 186.6–188.9° C. ¹H NMR(acetone-d₆, 300 MHz) 7.79 (s, 1H), 7.32 (m, 1H), 6.71 (m, 1H), 6.64(brs, 1H), 5.21 (m, 1H). ESHRMS m/z 278.0262 (M−H, Calc'd 278.0240).Anal. Calc'd for C₁₁H₆NO₂F₅+1.58% H₂O: C, 46.58; H, 2.31; N, 4.94.Found: C, 46.20; H, 2.07; N, 4.54.

EXAMPLE 160

6-Iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

Step 1. Preparation of ethyl6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

A mixture of 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol),diazbicyclo[2.2.2]-undec-7-ene (32.2 g, 212.0 mmol), and ethyl4,4,4-trifluorocrotonate (35.7 g, 212.0 mmol) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (48 mL) was heated at60° C. for 8 hours. The solution was cooled to room temperature and thesolution poured into ethyl acetate-hexanes (1:1, 500 mL). The solutionwas extracted with 2.5 N aqueous hydrochloric acid (2×200 mL), saturatedaqueous ammonium chloride (2×200 mL), dried over sodium sulfate,filtered and concentrated in vacuo. The resulting dark yellow oil wasdissolved in hexanes (100 mL) and fine yellow crystals formed uponstanding. Vacuum filtration of this suspension yielded ethyl6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as fineyellow crystals (19.3 g, 50% yield): mp 137–138° C. ¹H NMR (CDCl₃, 300MHz) 7.62 (s, 1H), 7.36–7.48 (m, 2H), 6.43 (d, J=8.2 Hz), 5.36 (brs,1H), 5.11 (q, 1H, J=7.1 Hz), 4.25–4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).ESHRMS m/z 395.9716 (M−H, Calc'd 395.9708).

Step 2. Preparation of6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

Hydrolysis of the ester (Step 1) was performed by a procedure similar tothat described in Example 157, Step 3, yielding the carboxylic acid.

.mp 188–192° C. ¹H NMR (CD₃OD/300 MHz) 7.668 (s, 1H), 7.46 (d, 1H, J=2.2Hz), 7.39 (dd, 1H, J=8.4, 2.2 Hz), 6.52 (d, 1H, J=8.4 Hz), 5.01 (q, 1H,J=7.5 Hz). ESHRMS m/z 367.9401 (M, Calc'd 367.9395).

EXAMPLE 161

6-Bromo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 160: mp 185–186° C. ¹H NMR(CD₃OD/300 MHz) 7.68 (s, 1H), 7.31 (d, 1H, J=2.2 Hz), 7.23 (dd, 1H,J=8.7, 2.2 Hz), 6.64 (d, 1H, J=8.7 Hz), 5.01. (q, 1H, J=7.5 Hz). EIHRMSm/z 319.9519 (M, Calc'd 319.9534). Anal. Calc'd for C₁₁H₇BrF₃NO₂: C,41.02; H, 2.19; N, 4.35; Found: C, 41.27, H, 2.23, N, 4.26.

EXAMPLE 162

1,2-Dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid

Step 1. Preparation of 2-amino-5-(trifluoromethoxy)benzoic acid.

5-(Trifluoromethoxy)isatin (15.0 g, 65 mmol) and potassium hydroxidepellets (4 g) were mixed in water (35 mL) and cooled to 0° C. Withvigorous stirring, a solution of 30% aqueous hydrogen peroxide (11.7 g),potassium hydroxide pellets (5.8 g), and water (80 mL) was addeddrop-wise keeping the temperature below 10° C. After stirring 1 hour at0° C., glacial acetic acid (22 mL) was added drop-wise, causing foamingand formation of a precipitate. The contents were stirred overnight andfiltered to afford the 2-amino-5-trifluoromethoxybenzoic acid as anamber solid (12.5 g, 87%). A small amount was recrystallized from ethylacetate-hexanes to afford amber needles for an analytical sample and theremaining compound was used without further purification: mp142.5–144.2° C. ¹H NMR (CDCl₃, 300 MHz) 7.98 (s, 1H), 7.18 (d, 1H, J=8.0Hz) 6.62 (d, 1H, J=8.0 Hz), 6.40 (brs, 2H). Anal. Calc'd for C₈H₆NO₃F₃:C, 43.45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35.

Step 2. Preparation of 2-amino-5-(trifluoromethoxy)benzyl alcohol.

The 2-amino-5-trifluoromethoxybenzoic acid (2.0 g, 9.0 mmol) intetrahydrofuran (20 mL) was added dropwise to borane methyl sulfidecomplex (1.5 mL, 15.0 mmol) in tetrahydrofuran (5 mL). The reaction wasrefluxed overnight and allowed to cool. A solution of 30% aqueoushydrogen peroxide (0.5 mL), 2.5 N sodium hydroxide (0.5 mL) and water(10 mL) was added drop-wise and the reaction stirred 0.5 hours. Afterdiluting with diethyl ether (50 mL), the organic layer was washed with0.1 M aqueous sodium meta-bisulfite (2×10 mL) and 2.5 N aqueous sodiumhydroxide (2×10 mL). The organic layer was diluted further with hexanes(50 mL) and washed with brine (2×20 mL), dried over anhydrous Na₂SO₄,and concentrated in vacuo leaving an amber oil (1.9 g) which solidified.The solid was recrystallized from ethyl acetate-hexanes to afford the2-amino-5-trifluoromethoxybenzyl alcohol as a light amber solid (1.44 g,77%): mp 75.9–77.6° C. ¹H NMR (CDCl₃, 300 MHz) 7.00 (m, 2H), 6.65 (d,1H, J=8.0 Hz), 4.05 (s, 2H), 3.25 (brs, 3H). ESHRMS m/z 208.0592 (M+H⁺,Calc'd 208.0585). Anal. Calc'd for C₈H₈NO₂F₃: C, 46.39; H, 3.89; N,6.76. Found: C, 46.61; H, 3.79; N, 6.71.

Step 3. Preparation of 2-amino-5-(trifluoromethoxy)-benzaldehyde.

The 2-amino-5-trifluoromethoxybenzyl alcohol from Step 2 (9.7 g, 47mmol) and manganese (IV) oxide (21 g, 240 mmol) were refluxed inchloroform (200 mL) for 1 hour. The contents were allowed to cool andfiltered. The filtrate was concentrated in vacuo leaving an amber oil(8.2 g) which solidified. The oil was distilled (bulb to bulb apparatus)at 50° C. (0.1 mm) to afford a yellow solid (7.2 g). The solid wasrecrystallized from hexanes to afford the desired2-amino-5-(trifluoromethoxy)-benzaldehyde as yellow crystals (4.4 g,46%): mp. 42–44° C. ¹H NMR (CDCl₃, 300 MHz) 9.81 (s, 1H), 7.36 (s, 1H),7.20 (d, 1H, J=9.0 Hz), 6.64 (d, 1H, J=9.0 Hz). EIHRMS m/z 205.0328 (M⁺,Calc'd 205.0350).

Step 4. Preparation of ethyl1.2-dihydro-6-(trifluoro-methoxy)-2(trifluoromethyl)-3-quinolinecarboxylate.

The 2-amino-5-(trifluoromethoxy)benzaldehyde from Step 3 (5.3 g, 26mmol), anhydrous potassium carbonate (6.9 g, 50 mmol), and ethyl4,4,4-trifluorocrotonate (7.7 mL, 50 mmol) were mixed in anhydrousdimethylformamide (50 mL) and heated at 90° C. for 6 hours. The reactionwas allowed to cool to room temperature and was partitioned betweenethyl acetate (200 mL) and water (200 mL). The aqueous layer wasextracted with more ethyl acetate (100 mL). The ethyl acetate extractswere combined and washed with brine (200 mL), dried over MgSO₄, andconcentrated in vacuo yielding an oil (9.6 g). The oil was purified byflash chromatography on silica gel, eluting with ethyl acetate-hexanes(1:1). Fractions containing the desired product were combined,concentrated in vacuo, and the residue recrystallized from ethylacetate-hexanes to afford the ethyl1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylateas a yellow solid (4.05 g, 32%): mp. 123–125° C. ¹H NMR (CDCl₃, 300 MHz)7.65 (s, 1H), 7.02 (m, 2H), 6.60 (m, 1H), 5.10 (m, 1H), 4.60 (brs, 1H),4.28 (m, 2H), 1.32 (t, 3H, J=7.0 Hz). ESHRMS m/z 356.0698 (M−H, Calc'd356.0721). Anal. Calc'd for C₁₄H₁₁NO₃F₆: C, 47.34; H, 3.12; N, 3.94.Found: C, 47.37; H, 3.04; N, 3.93.

Step 5. Preparation of1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid.

The ethyl1,2-dihydro-6-(trifluoromethoxy)-2(trifluoromethyl)-3-quinolinecarboxylatefrom Step 4 (880 mg, 2.5 mmol) and 2.5 N aqueous sodium hydroxide (2 mL)were mixed in methanol (15 mL) and water (15 mL). The solution washeated on a steam bath for 2 hours. The reaction was allowed to cool toroom temperature and was extracted with diethyl ether (50 mL). Theaqueous layer was acidified (pH=1) with 3 N HCl and extracted with ethylacetate (2×50 mL). The combined ethyl acetate extracts were dried overMgSO₄ and concentrated in vacuo leaving an oil. The oil was crystallizedfrom cold dichloromethane-hexanes to afford the1,2-dihydro-6-(trifluoromethoxy)-2(trifluoromethyl)-3-quinolinecarboxylicacid as yellow needles (0.727 g, 89%): mp 127.7–128.9° C. ¹H NMR (CDCl₃,300 MHz) 7.80 (s, 1H), 7.05 (m, 2H), 6.62 (d, 1H, J=8.0 Hz), 5.13 (m,1H), 4.62 (brs, 1H). ESHRMS m/z 326.0252 (M−H, Calc'd 326.0252). Anal.Calc'd for C₁₂H₇NO₃F₆: C, 44.05; H, 2.16; N, 4.28. Found: C, 43.89; H,2.04; N, 4.24.

EXAMPLE 163

6-(Trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

Step 1. Preparation ofN-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide.

A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g,199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0° C. under adry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) wasadded drop-wise over 2 hours, maintaining the temperature below 10° C.After the addition, the contents were allowed to warm to roomtemperature for 2 hours. The reaction was washed with water (2×200 mL),saturated ammonium chloride solution (2×200 mL), dried over sodiumsulfate and filtered. The solvent was removed in vacuo to afford a whitesolid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g,98%): mp 157–159° C. ¹H NMR (CDCl₃/300 MHz) 7.61 (ab, 4H, J=8.7, Δν=28.6Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H⁺, Calc'd246.1106). Anal. Calc'd for C₁₂H₁₄F₃NO: C, 58.77; H, 5.75; N, 5.71.Found: C, 58.28; H, 5.79; N, 5.65.

Step 2. Preparation ofN-[2-formyl-4-(trifluoromethyl)phenyl]-2,2-dimethyl propanamide.

A 1 liter three neck round bottom flask equipped with equalizingaddition funnel, magnetic stirer and temperature monitoring device wascharged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction waschilled to −78° C. under nitrogen followed by slow addition ofn-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, suchthat the temperature of the reaction did not rise above −65° C. Thecontents were held at −78° C. for one hour, 0° C. for two hours, thenchilled back to −78° C. Excess N,N-dimethylformamide (100 mL, 1.37 mol)was added. The contents were warmed to room temperature and stirred fortwo hours. Aqueous 1 N HCl was added to the reaction until the pHreached 1. The reaction was washed with water (2×200 mL), saturatedammonium chloride solution (2×200 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to afford a yellowsolid. The product was purified by flash chromatography (silica gel, 10%ethyl acetate, 90% hexanes) to yield, upon concentration of theappropriate fractions,N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid(7.36 g, 65%): mp 69–73° C. ¹H NMR (CDCl₃/300 MHz) 11.5 (br s, 1H), 9.99(s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H,),1.37 (s, 9H). ESHRMS m/z 274.1060 (M+H⁺, Calc'd 274.1055). Anal. Calc'dfor C₁₃H₁₄F₃NO₂: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43;N, 5.01.

Step 3. Preparation of ethyl6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

To a suspension of N-(2-formyl-4-(trifluoro-methylphenyl)-2,2-dimethylpropanamide (Step 2) (921 mg, 3.7 mol) and lithium hydride (115 mg, 14.5mmol) in dimethyl sulfoxide (10 mL) was added ethyl4,4,4-trifluorocrotonate (2.83 g, 16.8 mmol) and the contents warmed to30° C. for 4 hours. After the addition of ethyl acetate (50 mL), thereaction was washed with water (2×30 mL), saturated ammonium chloridesolution (2×30 mL), dried over sodium sulfate and filtered. The filtratewas concentrated in vacuo to afford a yellow solid. The product waspurified by flash chromatography (silica gel, eluant: ethylacetate-hexanes, 1:9) to yield, upon concentration of the appropriatefractions, ethyl6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylateas a yellow solid (65 mg, 5%): mp 138–139° C. ¹H NMR (CDCl₃/300 MHz)7.67 (s, 1H), 7.26 (s, 1H), 7.04 (d, 1H, J=6.6 Hz), 6.62 (m, 1H,), 5.14(m, 1H), 4.60 (brs, 1H), 4.32 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). ESHRMSm/z 338.0592 (M−H Calc'd 338.0616). Anal. Calc'd for C₁₃H₁₁F₃NO₂: C,49.57; H, 3.27; N, 4.13; Found: C, 49.23; H, 2.81; N, 3.93.

Step 4. Preparation of ethyl6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid.

Ethyl6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylatefrom Step 3 (45 mg, 0.13 mmol) was suspended inmethanol-tetrahydrofuran-water (10 mL, 7:2:1). Lithium hydroxide (24 mg,0.52 mmol) was added, and the mixture was gently heated to reflux fortwo hours. The reaction was cooled to room temperature and 1 N HCl addeduntil pH=1. The organic solvent was removed in vauco to afford asuspension of a crude yellow solid. Diethyl ether (20 mL) was added, andthe solution was washed with water (2×20 mL), saturated ammonium sulfate(2×20 mL), dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to yield6-trifluoromethyl-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid as a yellow solid, (0.041 g, 0.132 mmol, 99%): mp 150–156° C. ¹HNMR (CD₃OD/300 MHz) 7.78 (s, 1H), 7.48 (s, 1H), 7.40 (m, 1H), 6.81 (m,1H), 5.17 (m, 1H). ESHRMS m/z 310.0307 (M−H, Calc'd 310.0303).

EXAMPLE 164

6-Cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

Step 1. Preparation of ethyl6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate.

N,N-Dimethylformamide (5 mL) was degassed with nitrogen for thirtyminutes in a three neck round bottom flask equipped with a condenser,temperature monitoring, nitrogen purge and heating mantle. Ethyl6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) wereadded to the N,N-dimethylformamide and stirred vigorously for tenminutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.068 g, 0.53 mmol)was added and the contents gently warmed to 80° C. for 2 hours under anitrogen atmosphere. Ethyl acetate (20 mL) was added, followed byextraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfateand solvent removed in vacuo to yield a yellow solid. The product waspurified by flash chromatography (silica gel, ethyl acetate-hexanes,3:1) to yield, upon concentration of the appropriate fractions, ethyl6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as ayellow solid (188 mg, 48%): mp 211–212° C. ¹H NMR (CDCl₃/300 MHz) 7.68(s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s,1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH₄ ⁺,Calc'd 314.1116). Anal. Calc'd for C₁₄H₁₁F₃N₂O₂: C, 56.76; H, 3.74; N,9.46. Found: C, 56.44; H, 4.03; N, 9.29.

Step 2. Preparation of6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid.

To a suspension of ethyl6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (140 mg,0.45 mmol) in methanol-tetrahydrofuran-water (10 mL, 7:2:1) was addedlithium hydroxide (76 mg, 0.91 mmol) and the mixture gently heated toreflux for two hours. The contents were cooled to room temperature and 1N aqueous hydrochloric acid added until pH=1. The organic solvent wasremoved in vacuo to afford a suspension of crude yellow solid. Diethylether (20 mL) was added, and the solution was washed with water (2×20mL), saturated ammonium sulfate (2×20 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to yield6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid as ayellow solid, (116 mg, 95%): mp 238–240° C. ¹H NMR (CD₃OD/300 MHz) 7.75(s, 1H), 7.56 (m, 1H), 7.43 (m, 1H), 6.79 (d, 1H, J=8.5 Hz) 5.19 (q, 1H,J=7.1 Hz). EIHRMS m/z 267.0405 (M−H, Calc'd 267.0381). Anal. Calc'd forC₁₄H₁₁F₃N₂O₂: C, 53.74; H, 2.63; N, 10.45. Found: C, 53.99; H, 2.89; N,10.19.

EXAMPLE 165

6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid

Step 1. Preparation of ethyl6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylate.

Ethyl-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate(Example 157, Step 2) (1.28 g, 4.21 mmol), tetrabutylammonium iodide(0.36 g, 0.92 mmol) and aqueous NaOH(50%, 2 mL) were stirred vigorouslyin methylene chloride (40 mL). Dimethyl sulfate (2.12 g, 16.84 mmol) wasadded to the dark orange mixture via syringe over 2 hours. Hexane (5 mL)was added, and the solution was washed with water (2×20 mL), saturatedammonium chloride solution (2×20 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to afford the crudeester as a yellow solid. The solid was purified by flash chromatography(silica gel, 50 g; ethyl acetate-hexanes, 1:19) to yield, uponconcentration of the appropriate fractions, ethyl6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinoline-carboxylate(1.2 g, 90% yield): mp 118–120° C. ¹H NMR (CD₃OD/300 MHz) 7.71 (s, 1H),7.30–7.26 (m, 2H), 6.77–6.74 (m, 1H), 5.12 (q, 1H, J=6.8 Hz), 4.44–4.22(m, 2H), 3.18 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). EIHRMS m/z 320.0701 (M−H,Calc'd 320.0665) Anal. Calc'd for C₁₄H₁₃F₃NO₂Cl: C, 52.60; H, 4.10; N,4.38. Found: C, 52.57; H, 4.14; N, 4.32.

Step 2. Preparation of6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid

Ethyl6-chloro-1,2-dihydro-1-methyl-2-(trifluoro-methyl)-3-quinolinecarboxylate(1.21 g, 3.78 mmol) was suspended in methanol-tetrahyrofuran-water (20mL, 7:2:1). Lithium hydroxide (0.262 g, 6.24 mmol) was added, and themixture was gently heated to reflux for two hours. The reaction wascooled to room temperature and 1 N HCl added until pH=1. The organicsolvent was removed in vauco to afford a suspension of crude yellowsolid. Diethyl ether (20 mL) was added, and the resulting solution waswashed with water (2×20 mL), saturated ammonium chloride (2×20 mL),dried over sodium sulfate and filtered. The filtrate was concentrated invacuo to afford the product as a yellow solid,6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinoline-carboxylicacid. (1.08 g, 98% yield): mp 208–209° C. ¹H NMR (CD₃OD/300 MHz) 7.69(d, 1H, J=2.5 Hz), 7.28–7.24 (m, 2H), 6.73 (dd, 1H, J=9.5, 2.5 Hz), 5.13(q, 1H, J=7.0), 3.16 (s, 3H). Anal. Calc'd for C₁₂H₉F₃NO₂Cl: C, 49.42;H, 3.11; N, 4.80; Cl, 12.16. Found: C, 49.88; H, 3.29; N, 4.59; Cl,12.42

EXAMPLE 166

6-Chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylicacid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 165: mp 229–231° C. ¹H NMR(CD₃OD/300 MHz) 7.77 (s, 1H), 7.58 (d, 2H, J=8.0 Hz), 7.39 (d, 2H, J=8.0Hz), 7.30 (d, 1H, J=2.4), 7.13 (dd, 1H, J=8.9, 2.4 Hz), 6.75 (d, 1H,J=8.9 Hz), 5.27 (q, 1H, J=7.0 Hz), 4.90 (ab, 2H, J=16.7 Hz, Δν=95.2 Hz).EIHRMS m/z 434.0401 (Calc'd for M−H 434.0383) Anal. Calc'd forC₁₉H₁₄F₆NO₂Cl: C, 52.13; H, 3.22; N, 3.22; Found: C, 52.36; H, 2.91; N,3.21.

EXAMPLE 167

6-Chloro-1-[(4-chlorophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 165: mp 250–253° C. ¹H NMR(CD₃OD/300 MHz) 7.74 (s, 1H), 7.32–7.13 (m, 6H), 6.76 (d, 1H, J=8.7 Hz),5.22 (q, 1H, J=7.0 Hz), 4.81 (ab, 2H, J=16.3 Hz, Δν=54.7 Hz). ESHRMS m/z400.0105 (M−H, Calc'd 400.0119).

EXAMPLE 168

6-Chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylicacid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 165: mp 196–197° C. ¹H NMR(CD₃OD/300 MHz) 7.71 (s, 1H), 7.27–7.26 (m, 1H), 7.18–7.12 (m, 3H),6.85–6.81 (m, 3H), 5.16 (q, 1H, J=7.1 Hz), 4.69 (ab, 2H, J=15.3 Hz,Δν=111.8 Hz), 3.73 (s, 3H). ESHRMS m/z 396.0625 (M−H, Calc'd 396.0614).Anal. Calc'd for C₁₉H₁₄F₆NO₂Cl: C, 52.13; H, 3.22; N, 3.22. Found: C,52.36; H, 2.91; N, 3.21.

EXAMPLE 169

6-Chloro-1-[(4-cyanophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 165: mp 258–260° C. ¹H NMR(CD₃OD/300 MHz) 7.78 (S, 1H), 7.66 (d, 2H, J=8.2 Hz), 7.41 (d, 2H, J=8.2Hz), 7.33 (d, 1H, J=2.7 Hz), 7.15 (dd, 1H, J=8.7, 2.7 Hz), 6.71 (d, 1H,J=8.7 Hz), 5.31 (q, 1H, J=7.0 Hz), 4.94 (ab, 2H, J=17.1, Δν=91.8 Hz).ESHRMS m/z 391.0443 (M−H, Calc'd 391.0461). Anal. Calc'd forC₁₉H₁₂F₃N₂O₂Cl+0.53% H₂O: C, 57.79; H, 3.55; N, 7.09; Found: C, 57.26;H, 3.17; N, 6.78.

EXAMPLE 170

6-Chloro-1,2-dihydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylicacid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 165: mp 225–228° C. ¹H NMR(CD₃OD-3% TFA/300 MHz) 8.14 (d, 2H, J=8.8 Hz), 7.77 (s, 1H), 7.42 (d,2H, J=8.8 Hz), 7.29 (d, 1H, J=2.4 Hz), 7.11 (dd, 1H, J=8.9, 2.4 Hz),6.67 (d, 1H, J=8.9 Hz), 5.27 (q, 1H, J=6.8 Hz), 4.93 (ab, 2H, J=17.2 Hz,Δν=95.0 Hz). ESHRMS m/z 411.0327 (M−H, Calc'd 411.0359).

EXAMPLE 171

6-Chloro-1,2-dihydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a proceduresimilar to that described in Example 165: mp 201–202° C. ¹H NMR(CD₃OD/300 MHz) 7.67 (s, 1H), 7.25–7.22 (m, 2H), 6.86 (d, 1H, J=8.7 Hz),5.21 (q, 1H, J=7.0 Hz), 3.81–3.71 (m, 1H), 3.47–3.39 (m, 1H), 1.20 (t,3H, J=7.2 Hz). ESHRMS m/z 304.0360 (M−H, Calc'd 304.0352).

EXAMPLE 172

(S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid

To a solution of6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid(Example 157) (6.75 g, 24.3 mmol) in ethyl acetate (25 mL) was added(S)-(−)-α-methylbenzylamine (1.50 g, 12.2 mmol). To the resultingsolution was added hexanes (50 mL) with mixing. Stirring wasdiscontinued and the reaction held static at room temperature for 16hours during which time yellow crystals formed. The crystals werecollected and washed with ethyl acetate-hexanes (100 mL, 1:2). Theresulting yellow solid (932 mg) was dissolved in ethyl acetate (20 mL)and extracted with 1 N HCl (3×10 mL). The organic layer was dried oversodium sulfate and solvent removed at reduced pressure. The(s)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acidwas obtained as a yellow solid (648 mg, 10% yield). mp 173–176° C. ¹HNMR (acetone-d₆, 300 MHz) 7.80 (s, 1H), 7.35 (d, 1H, J=2.2 Hz), 7.18 (d,1H, J=8.0, J=2.2 Hz-) 6.86 (d, 1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m,1H). Anal. Calc'd. for C₁₁H₇NO₂F₃Cl C, 47.40; H, 2.54; N, 5.40. Found C,47.49; H, 2.60; N, 4.98. The compound was determined to have an opticalpurity greater than 90% ee. Optical purity was determined by HPLC asdescribed in Example 66.

EXAMPLE 173

6-(2,2,2-Trifluoro-1-hydroxyethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid

Step 1. Preparation of ethyl6-(1-hydroxy-2,2,2-trifluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

The aldehyde (Example 75, Step 1) (0.89 g, 3.0 mmol) was cooled to 0° C.and treated with a 0.5 M solution of trimethyl(trifluoromethyl)silane(8.4 mL, 4.2 mmol) and four drops of a 1.0M solution oftetrabutylammonium fluoride was added. The reaction was allowed to warmto room temperature and stirred for 21.1 hours. The reaction wasquenched with 3 N HCl, extracted with ethyl acetate, washed with water,brine, dried over MgSO₄, and concentrated in vacuo to give a brown oil(1.02 g). This oil was purified by flash chromatography over silica gel,eluting with 10% ethyl acetate/hexanes to afford a brown oil (0.77 g,58%): ¹H NMR (CDCl₃/300 MHz) 7.72 (d, 1H, J=3.4 Hz), 7.34 (m, 2H), 6.99(d, 1H, J=8.5 Hz), 5.71 (q, 1H, J=6.8 Hz), 4.83 (q, 1H, J=6.4 Hz), 4.33(m, 2H), 1.35 (t, 3H, J=7.1 Hz), 0.11 (s, 9H). FABLRMS m/z 443 (M+H).

Step 2. Preparation of6-(1-hydroxy-2,2,2-trifluoroethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylicacid.

The ester from Step 1 (0.15 g 0.34 mmol) was dissolved in THF (2 mL) andethanol (2 mL), treated with 2.5 N NaOH (1 mL, 2.5 mmol), and stirred atroom temperature for 18.6 hours. The reaction mixture was concentratedin vacuo, acidified with 3 N HCl, extracted with ethyl acetate, washedwith 3 N HCl, brine, dried over MgSO₄, and concentrated in vacuo to givea yellow oil which was recrystallized from ethyl acetate/hexane to yielda white solid (0.03 g, 25%): mp 114–120° C. ¹H NMR (acetone-d₆/300 MHz)7.94 (s, 1H), 7.65 (s, 1H), 7.60 (dd, 1H, J=8.2 Hz 2.0 Hz), 7.11 (d, 1H,J=8.3 Hz), 5.87 (q, 1H, J=7.0 Hz), 5.24 (q, 1H, J=7.0 Hz). FABLRMS m/z341 (M−H). ESHRMS m/z 341.0241 (M−H, Calc'd 341.0249).

EXAMPLE 174

6-Chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylicacid

Step 1. Preparation of N-[5-chloropyridin-2-yl-2,2-dimethylpropanamide.

To 2-amino-5-chloropyridine (10.0 g, 0.078 mol) (Aldrich) andtriethylamine (12 mL, 0.086 mol) in methylene chloride (200 mL), at 0°C., was added dropwise trimethylacetyl chloride in methylene chloride(15 mL). The reaction was allowed to warm to room temperature whilestirring overnight. The resulting mixture was washed with water, brine,and was dried over MgSO₄ and filtered. Concentration of the filtrate invacuo provided a colorless oil (19.2 g). The oil was dissolved inhexanes and cooled causing the precipitation of a solid. The solid wascollected by filtration affording the amide as a white solid (14.96 g,90%): mp 51.4–53.4° C. ¹H NMR (CDCl₃/300 MHz) 8.25–8.15 (m, 2H), 8.00(br s, 1H), 7.68–7.60 (m, 1H), 1.28 (s, 9H). Anal. Calc'd forC₁₀H₁₃N₂OCl: C, 56.47; H, 6.16; N, 13.17 Found: C, 56.72; H, 6.34; N,12.88.

Step 2. Preparation ofN-[5-chloro-3-formylpyridin-2-yl]-2,2-dimethylpropanamide.

To a chilled (−78° C.), stirred solution of the amide (Step 1) (5.0 g,0.024 mole) in tetrahydrofuran (100 mL) was added t-butyl lithium (1.7Min pentane, 32.4 mL, 0.055 mole) dropwise. Dimethylformamide (2.3 mL,0.03 mole) was added dropwise at −78° C. over 3 hours and the mixtureallowed to warm room temperature. The reaction was quenched with icewater (200 mL) and extracted with ethyl acetate. The resulting organicphase was dried over MgSO₄ and was concentrated in vacuo to a volume of20 mL. A white solid precipitated which was collected by filtrationyielding the formylated product (3.24 g, 56%): mp 168.7–170.8° C. ¹H NMR(CDCl₃/300 MHz) 10.60(br s, 1H), 9.88 (s, 1H), 8.57 (s, 1H), 8.00 (s,1H), 1.28 (s, 9H). Anal. Calc'd for C₁₁H₁₃N₂O₂Cl: C, 54.89; H, 5.44; N,11.64 Found: C, 54.87; H, 5.42; N, 11.40.

Step 3. Preparation 2-amino-5-chloro-3-formylpyridine.

The product of Step 2 (2.7 g, 11 mmol) and 3 N HCl (50 mL) were heatedat reflux for 2 hours. The reaction was allowed to cool to roomtemperature and was concentrated in vacuo yielding a light yellow solid(2.1 g). The solid was partitioned between ethyl acetate and 2.5 N NaOHsolution. The ethyl acetate layer was dried over MgSO₄ and concentratedin vacuo providing a solid (1.7 g). The solid was recrystallized fromethyl acetate to give the desired substituted pyridine as yellow needles(1.2 g, 68%): mp 176.1–177.3° C. ¹H NMR (CDCl₃/300 MHz) 9.80 (s, 1H),8.21 (s, 1H), 7.75 (s, 1H), 6.75 (br s, 2H). Anal. Calc'd for C₆H₅N₂OCl:C, 46.03; H, 3.22; N, 17.89 Found: C, 45.90; H, 3.24; N, 17.80.

Step 4. Preparation of ethyl6-chloro-2-(triflouromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylate.

The substituted pyridine from Step 3 (1.7 g, 11 mmol), anhydrouspotassium carbonate (3.0 g, 22 mmol), and ethyl 4,4,4-trifluorocrotonate(3.3 mL, 22 mmol) were mixed in anhydrous dimethylformamide (20 mL) andheated at 80° C. for 2 hours. The reaction was allowed to cool to roomtemperature and was partitioned between ethyl acetate (100 mL) and water(100 mL). The aqueous layer was extracted with more ethyl acetate (100mL). The combined organic extracts were washed with brine (100 mL),dried over MgSO₄, and concentrated in vacuo yielding a waxy amber solidThe solid was triturated with diethyl ether providing the ester as ayellow solid (613 mg, 18%). A small amount was recrystallized from ethylacetate for analytical data: mp 180.1–181.9° C. ¹H NMR (CDCl₃/300 MHz)7.99 (s, 1H), 7.61 (s, 1H); 7.39 (s, 1H), 6.00 (br s, 1H), 5.33–5.20 (m,1H), 4.40–4.23 (m, 2H), 1.40–1.30 (m, 3H). Anal. Calc'd forC₁₂H₁₀N₂O₂F₃Cl: C, 47.00; H, 3.29; N, 9.13 Found: C, 46.83; H, 3.03; N,9.18.

Step 5. Preparation of6-chloro-2-(trifluoromethyl)-1,2-dihydro[1,8]napthyridine-3-carboxylicacid.

The ester from Step 4 (1.3 g, 4.4 mmol) and 2.5 N sodium hydroxidesolution (3.5 mL, 9 mmol) were mixed in tetrahydrofuran (25 mL),methanol (10 mL), and water (25 mL). The mixture was heated at 50° C.for 4 hours, allowed to cool to room temperature, and was concentratedin vacuo to remove the tetrahydrofuran and methanol. The resultingaqueous solution was washed with diethyl ether (2×100 mL). The aqueousphase was acidified with 3 N HCl causing the precipitation of a yellowsolid (1.1 g). The solid was triturated with ethanol-acetone andcollected by vacuum filtration providing the title compound as a yellowsolid (276 mg, 23%): mp 287.4–288.4° C. ¹H NMR (acetone-d6/300 MHz)11.50 (br s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.28 (br s,1H), 5.42–5.30 (m, 1H). Anal. Calc'd for C₁₀H₆N₂O₂F₃Cl: C, 43.11; H,2.17; N, 10.05 Found: C, 42.88; H, 2.03; N, 10.06.

EXAMPLE 175

(S)-6,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

6,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid(Example 32) (300 g, 1.04 mol) was added to ethyl acetate (750 mL). Themixture was stirred for 5 minutes, warmed to 70° C. and held at thistemperature for 5 minutes. The resulting solution was cooled to 50° C.and (s)-(−)-α-methylbenzylamine (58 g, 0.48 mol) was added. Heptane(1880 mL) was added and the mixture stirred for 0.5 hour, then stirringwas discontinued. The reaction was allowed to cool to 22° C. and standfor 8 hours. The salt crystallized during this time and was collected byvacuum filtration. The solid was washed with ethyl acetate-heptane (1:3,2×50 mL). The solid obtained was dried at 40° C. under vacuum (20 mm)for 24 hours to give the salt (35 g, 16%).

A three-neck 2 L round bottom flask was purged with nitrogen and wascharged with deionized water (750 mL) and the salt (103 g, 0.24 mole;This material was obtained using a similar procedure to that describedabove). To the resulting stirred suspension was added concentrated HCl(37 mL) drop-wise over 0.5 hours with good stirring below 20° C. causingthe free carboxylic acid to precipitate. After stirring for 2 hours, thesuspension was vacuum filtered and the solid washed with deionized water(5×50 mL; until the washings were neutral). The solid was dried at 40°C. under vacuum (20 mm) for 12 hours yielding the title compound as asolid (74 g, 100%): mp 166.0–168.4° C. 1H NMR (acetone-d₆/300 MHz) 7.94(s, 1H), 7.60 (s, 2H), 6.04 (q, 1H, J=6.8 Hz). ESHRMS m/z 310.9489 (M−H,Calc'd 310.9450). This compound was determined to have an optical purityof greater than 90% ee. The optical purity was determined by the methoddescribed in Example 66.

BIOLOGICAL EVALUATION

Rat Carrageenan Foot Pad Edema Test

The carrageenan foot edema test was performed with materials, reagentsand procedures essentially as described by Winter, et al., (Proc. Soc.Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats wereselected in each group so that the average body weight was as close aspossible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenan,the volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined (Otterness and Bliven, Laboratory Models for Testing NSAIDs,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).The % inhibition shows the % decrease from control paw volume determinedin this procedure and the data for selected compounds in this inventionare summarized in Table I.

TABLE I RAT PAW EDEMA ANALGESIA % Inhibition % Inhibition @ 30 mg/kg @30 mg/kg Example body weight body weight 1 57 58Evaluation of COX-1 and COX-2 Activity In Vitro

The compounds of this invention exhibited inhibition in vitro of COX-2.The COX-2 inhibition activity of the compounds of this inventionillustrated in the Examples was determined by the following methods.

a. Preparation of Recombinant COX Baculoviruses

Recombinant COX-1 and COX-2 were prepared as described by Gierse et al,[J. Biochem., 305, 479–84 (1995)]. A 2.0 kb fragment containing thecoding region of either human or murine COX-1 or human or murine COX-2was cloned into a BamH1 site of the baculovirus transfer vector pVL1393(Invitrogen) to generate the baculovirus transfer vectors for COX-1 andCOX-2 in a manner similar to the method of D. R. O'Reilly et al(Baculovirus Expression Vectors: A Laboratory Manual (1992)).Recombinant baculoviruses were isolated by transfecting 4 μg ofbaculovirus transfer vector DNA into SF9 insect cells (2×10⁸) along with200 ng of linearized baculovirus plasmid DNA by the calcium phosphatemethod. See M. D. Summers and G. E. Smith, A Manual of Methods forBaculovirus Vectors and Insect Cell Culture Procedures, Texas Agric.Exp. Station Bull. 1555 (1987). Recombinant viruses were purified bythree rounds of plaque purification and high titer (10⁷–10⁸ pfu/mL)stocks of virus were prepared. For large scale production, SF9 insectcells were infected in 10 liter fermentors (0.5×10⁶/mL) with therecombinant baculovirus stock such that the multiplicity of infectionwas 0.1. After 72 hours the cells were centrifuged and the cell pellethomogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1%3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. (CHAPS). Thehomogenate was centrifuged at 10,000×G for 30 minutes, and the resultantsupernatant was stored at −80° C. before being assayed for COX activity.

b. Assay for COX-1 and COX-2 Activity

COX activity was assayed as PGE₂ formed/μg protein/time using an ELISAto detect the prostaglandin released. CHAPS-solubilized insect cellmembranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (50 mM, pH 8.0) containing epinephrine,phenol, and heme with the addition of arachidonic acid (10 μM).Compounds were pre-incubated with the enzyme for 10–20 minutes prior tothe addition of arachidonic acid. Any reaction between the arachidonicacid and the enzyme was stopped after ten minutes at 37° C./roomtemperature by transferring 40 μl of reaction mix into 160 μl ELISAbuffer and 25 μM indomethacin. The PGE₂ formed was measured by standardELISA technology (Cayman Chemical). Results are shown in Table II.

c. Fast Assay for COX-1 and COX-2 Activity

COX activity was assayed as PGE₂ formed/μg protein/time using an ELISAto detect the prostaglandin released. CHAPS-solubilized insect cellmembranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (0.05 M Potassium phosphate, pH 7.5, 2 μMphenol, 1 μM heme, 300 μM epinephrine) with the addition of 20 μl of 100μM arachidonic acid (10 μM). Compounds were pre-incubated with theenzyme for 10 minutes at 25° C. prior to the addition of arachidonicacid. Any reaction between the arachidonic acid and the enzyme wasstopped after two minutes at 37° C./room temperature by transferring 40μl of reaction mix into 160 μl ELISA buffer and 25 μM indomethacin. ThePGE₂ formed was measured by standard ELISA technology (Cayman Chemical).Results are shown in Table II.

TABLE II COX-2* COX-1* COX-2 COX-1 Example IC₅₀ μM IC₅₀ μM IC₅₀ μM IC₅₀μM 1 0.3 45 2 <0.1 78 <0.1 5.0 6 <0.1 >100 7 0.1 16 <0.1 1.0 8 <0.1 61<0.1 21 9 <0.1 1.4 <0.1 <0.1 12 7 55 13 .3 >100 14 >100 >100 15 >0.1 11133.6 44 16 <0.1 24 1.4 51 18 12 >100 21 11 3.5 22 >100 >100 23 7 >10024 >100 25 >100 78 26 >100 20 27 67 >100 29 <0.1 >100 30 <0.1 1.2 16 3.831 <0.1 94 32 0.3 31 0.3 0.7 33 <0.1 5.7 8.2 28 35 2.2 8.9 1.7 11 38 0.26.2 25.7 57 39 0.2 45 1.3 >100 40 <0.1 24 74 43 42 <0.1 2.3 <0.1 11 4399 85 44 0.3 72 21 >100 45 0.2 47 46 >100 46 0.2 24 74 43 47 1.9 311.7 >100 49 24 >100 31 >100 50 79 >100 52 20 >100 53 8 13 6 >100 5419 >100 55 46 >100 53 >100 56 12 >100 29 >100 57 21 10 21 >100 5943 >100 63 1.4 >100 65 <0.1 1.0 66 82 38 <0.1 16.9 67 <0.1 30 <0.1 6.781 <0.1 10.5 <0.1 1.6 82 <0.1 16 <0.1 5.6 83 <0.1 9.6 <0.1 1.4 84 0.1 25<0.1 2.8 88 <0.1 12.4 <0.1 6.4 91 <0.1 23 0.2 36 96 0.2 >100 0.3 100 970.2 78 0.1 25 98 2.0 >100 1.5 19 99 0.2 36 <0.1 23 101 <0.1 18 <0.1 16103 36 61 104 <0.1 24 <0.1 8.2 105 0.3 4.5 0.2 0.1 106 0.2 21 <0.1 5.7114 <0.1 <0.1 <0.1 <0.1 115 <0.1 <0.1 <0.1 <0.1 116 <0.1 <0.1 <0.1 <0.1120 <0.1 98 <0.1 33 125 <0.1 0.2 <0.1 <0.1 129 0.2 2.6 <0.1 0.3 138 0.342.5 <0.1 11.1 152 <0.1 74 <0.1 10 154 0.5 68.5 <0.1 37 155 <0.1 1.6<0.1 <0.1 156 <0.1 0.8 <0.1 0.1 *fast assay

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I in associationwith one or more non-toxic, pharmaceutically-acceptable carriers and/ordiluents and/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. The activecompounds of the present invention may be administered by any suitableroute, preferably in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended. Theactive compounds and composition may, for example, be administeredorally, intravascularly, intraperitoneally, subcutaneously,intramuscularly or topically.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acyclooxygenase-2 inhibitor agent and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

The phrase “therapeutically-effective” is intended to qualify the amountof each agent which will achieve the goal of improvement in diseaseseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds which are administeredand the dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention depends on a variety offactors, including the age, weight, sex and medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may varywidely. The pharmaceutical compositions may contain active ingredientsin the range of about 0.1 to 2000 mg, preferably in the range of about0.5 to 500 mg and most preferably between about 1 and 100 mg. A dailydose of about 0.01 to 100 mg/kg body weight, preferably between about0.5 and about 20 mg/kg body weight and most preferably between about 0.1to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day.

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

For inflammations of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream, or as a suppository, containing the active ingredients in a totalamount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w andmost preferably 0.4 to 15% w/w. When formulated in an ointment, theactive ingredients may be employed with either paraffinic or awater-miscible ointment base. Alternatively, the active ingredients maybe formulated in a cream with an oil-in-water cream base. If desired,the aqueous phase of the cream base may include, for example at least30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof. The topical formulation may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethylsulfoxide and relatedanalogs. The compounds of this invention can also be administered by atransdermal device. Preferably topical administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w.

For therapeutic purposes, the active compounds of this combinationinvention are ordinarily combined with one or more adjuvants appropriateto the indicated route of administration. If administered per os, thecompounds may be admixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

All mentioned references are incorporated by reference as if herewritten. The priority document, U.S. Ser. No. 60/044,485 is alsoincorporated by reference.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

1. A compound of Formula I′

wherein X is NR^(a); wherein R^(a) is selected from hydrido,C₁–C₃-alkyl, (optionally substituted phenyl)-C₁–C₃-alkyl, acyl andcarboxy-C₁–C₆-alkyl; wherein R is selected from carboxyl, aminocarbonyl,C₁–C₆-alkylsulfonylaminocarbonyl and C₁–C₆-alkoxycarbonyl; wherein R″ isselected from hydrido, phenyl, thienyl and C₂–C₆-alkenyl; wherein R¹ isselected from C₁–C₃-perfluoroalkyl, chloro, C₁–C₆-alkylthio,C₁–C₆-alkoxy, nitro, cyano and cyano-C₁–C₃-alkyl; wherein R² is one ormore radicals independently selected from hydrido, halo, C₁–C₆-alkyl,C₂–C₆-alkenyl, C₂–C₆-alkynyl, halo-C₂–C₆-alkynyl, aryl-C₁–C₃-alkyl,aryl-C₂–C₆-alkynyl, aryl-C₂–C₆-alkenyl, C₁–C₆-alkoxy, methylenedioxy,C₁–C₆-alkylthio, C₁–C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl,heteroaryloxy, C₁–C₆-alkoxy-C₁–C₆-alkyl, aryl-C₁–C₆-alkyloxy,heteroaryl-C₁–C₆-alkyloxy, aryl-C₁–C₆-alkoxy-C₁–C₆-alkyl,C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy, C₁–C₆-haloalkylthio,C₁–C₆-haloalkylsulfinyl, C₁–C₆-haloalkylsulfonyl,C₁–C₃-(haloalkyl-C₁–C₃-hydroxyalkyl, C₁–C₆-hydroxyalkyl,hydroxyimino-C₁–C₆-alkyl, C₁–C₆-alkylamino, arylamino,aryl-C₁–C₆-alkylamino, heteroarylamino, heteroaryl-C₁–C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁–C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁–C₆-alkylaminosulfonyl, heteroaryl-C₁–C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, aryl-C₁–C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁–C₆-alkylcarbonyl, heteroaryl-C₁–C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁–C₆-alkoxycarbonyl,formyl, C₁–C₆-haloalkylcarbonyl and C₁–C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least two of A¹, A², A³ and A⁴ arecarbon; or wherein R² together with ring A forms a radical selected fromnaphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl anddibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.2. A compound of claim 1 wherein X is NR^(a); wherein R^(a) is selectedfrom hydrido, C₁–C₃-alkyl, (optionally substituted phenyl)-C₁–C₃-alkyl,acyl and carboxy-C₁–C₆-alkyl; wherein R is selected from carboxyl,aminocarbonyl, C₁–C₆-alkylsulfonylaminocarbonyl andC₁–C₆-alkoxycarbonyl; wherein R″ is selected from hydrido, phenyl,thienyl and C₂–C₆-alkenyl; wherein R¹ is selected fromC₁–C₃-perfluoroalkyl, chloro, C₁–C₆-alkylthio, C₁–C₆-alkoxy, nitro,cyano and cyano-C₁–C₃-alkyl; wherein R² is one or more radicalsindependently selected from hydrido, halo, C₁–C₆-alkyl, C₂–C₆-alkenyl,C₂–C₆-alkynyl, halo-C₂–C₆-alkynyl, aryl-C₁–C₃-alkyl, aryl-C₂–C₆-alkynyl,aryl-C₂–C₆-alkenyl, C₁–C₆-alkoxy, methylenedioxy, C₁–C₆-alkylthio,C₁–C₆-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy,C₁–C₆-alkoxy-C₁–C₆-alkyl, aryl-C₁–C₆-alkyloxy,heteroaryl-C₁–C₆-alkyloxy, aryl-C₁–C₆-alkoxy-C₁–C₆-alkyl,C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy, C₁–C₆-haloalkylthio,C₁–C₆-haloalkylsulfinyl, C₁–C₆-haloalkylsulfonyl,C₁–C₃-(haloalkyl-C₁–C₃-hydroxyalkyl, C₁–C₆-hydroxyalkyl,hydroxyimino-C₁–C₆-alkyl, C₁–C₆-alkylamino, arylamino,aryl-C₁–C₆-alkylamino, heteroarylamino, heteroaryl-C₁–C₆-alkylamino,nitro, cyano, amino, aminosulfonyl, C₁–C₆-alkylaminosulfonyl,arylaminosulfonyl, heteroarylaminosulfonyl,aryl-C₁–C₆-alkylaminosulfonyl, heteroaryl-C₁–C₆-alkylaminosulfonyl,heterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, aryl-C₁–C₆-alkylsulfonyl,optionally substituted aryl, optionally substituted heteroaryl,aryl-C₁–C₆-alkylcarbonyl, heteroaryl-C₁–C₆-alkylcarbonyl,heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C₁–C₆-alkoxycarbonyl,formyl, C₁–C₆-haloalkylcarbonyl and C₁–C₆-alkylcarbonyl; and wherein theA ring atoms A¹, A², A³ and A⁴ are independently selected from carbonand nitrogen with the proviso that at least three of A¹, A², A³ and A⁴are carbon; or wherein R² together with ring A forms a naphthyl orquinolyl radical; or an isomer or pharmaceutically acceptable saltthereof.
 3. A compound of claim 2 wherein X is NR^(a); wherein R^(a) isselected from hydrido, C₁–C₃-alkyl and (optionally substitutedphenyl)methyl; wherein R is carboxyl; wherein R″ is selected fromhydrido and C₂–C₆-alkenyl; wherein R¹ is selected fromC₁–C₃-perfluoroalkyl; wherein R² is one or more radicals independentlyselected from hydrido, halo, C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl,halo-C₂–C₆-alkynyl, phenyl-C₁–C₆-alkyl, phenyl-C₂–C₆-alkynyl,phenyl-C₂–C₆-alkenyl, C₁–C₃-alkoxy, methylenedioxy,C₁–C₃-alkoxy-C₁–C₃-alkyl, C₁–C₃-alkylthio, C₁–C₃-alkylsulfinyl,phenyloxy, phenylthio, phenylsulfinyl,C₁–C₃-haloalkyl-C₁–C₃-hydroxyalkyl, phenyl-C₁–C₃-alkyloxy-C₁–C₃-alkyl,C₁–C₃-haloalkyl, C₁–C₃-haloalkoxy, C₁–C₃-haloalkylthio,C₁–C₃-hydroxyalkyl, C₁–C₃-alkoxy-C₁–C₃-alkyl, hydroxyimino-C₁–C₃-alkyl,C₁–C₆-alkylamino, nitro, cyano, amino, aminosulfonyl,N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl,N-(phenyl-C₁–C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁–C₆-alkyl)aminosulfonyl, phenyl-C₁–C₃-alkylsulfonyl, 5-to 8-membered heterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, optionallysubstituted phenyl, optionally substituted 5- to 9-membered heteroaryl,phenyl-C₁–C₆-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl,4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl,4-methoxyphenylcarbonyl, aminocarbonyl, formyl, and C₁–C₆-alkylcarbonyl;wherein the A ring atoms A¹, A², A³ and A⁴ are independently selectedfrom carbon and nitrogen with the proviso that at least three of A¹, A²,A³ and A⁴ are carbon; or wherein R² together with ring A forms anaphthyl, benzofurylphenyl, or quinolyl radical; or an isomer orpharmaceutically acceptable salt thereof.
 4. A compound of claim 3wherein X is NR^(a); wherein R^(a) is selected from hydrido, methyl,ethyl, (4-trifluoromethyl)benzyl, (4-chloromethyl)benzyl,(4-methoxy)benzyl, and (4-cyano)benzyl, (4-nitro)benzyl; wherein R iscarboxyl; wherein R″ is selected from hydrido and ethenyl; wherein R¹ isselected from trifluoromethyl and pentafluoroethyl; wherein R² is one ormore radicals independently selected from hydrido, chloro, bromo,fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl,1-pentynyl, 3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, nitro, cyano, amino, aminosulfonyl,N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl,N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl,phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenylsubstituted with one or more radicals selected from chloro, fluoro,bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl,thienyl substituted with chloro, furyl, furyl substituted with chloro,benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl,formyl and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴are independently selected from carbon and nitrogen with the provisothat at least three of A¹, A², A³ and A⁴ are carbon; or wherein R²together with ring A forms a naphthyl, or quinolyl radical; or an isomeror pharmaceutically acceptable salt thereof.
 5. A compound of claim 2wherein X is NR^(a); wherein R^(a) is selected from hydrido,C₁–C₃-alkyl, phenyl-C₁–C₃-alkyl, acyl and carboxy-C₁–C₃-alkyl; wherein Ris carboxyl; wherein R¹ is selected from C₁–C₃-perfluoroalkyl; whereinR² is one or more radicals independently selected from hydrido, halo,C₁–C₆-alkyl, phenyl-C₁–C₆-alkyl, phenyl-C₂–C₆-alkynyl,phenyl-C₂–C₆-alkenyl, C₁–C₆-alkoxy, phenyloxy, 5- or 6-memberedheteroaryloxy, phenyl-C₁–C₆-alkyloxy, 5- or 6-memberedheteroaryl-C₁–C₆-alkyloxy, C₁–C₆-haloalkyl, C₁–C₆-haloalkoxy,C₁–C₆-alkylamino, N-phenylamino, N-(phenyl-C₁–C₆-alkyl)amino,N-heteroarylamino, N-(heteroaryl-C₁–C₆-alkylamino, nitro, amino,aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl,N-heteroarylaminosulfonyl, N-(phenyl-C₁–C₆-alkyl)aminosulfonyl,N-(heteroaryl-C₁–C₆-alkyl)aminosulfonyl, 5- to 8-memberedheterocyclylsulfonyl, C₁–C₆-alkylsulfonyl, optionally substitutedphenyl, optionally substituted 5- or 6-membered heteroaryl,phenyl-C₁–C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl,aminocarbonyl, and C₁–C₆-alkylcarbonyl; wherein the A ring atoms A¹, A²,A³ and A⁴ are independently selected from carbon and nitrogen with theproviso that at least three of A¹, A², A³ and A⁴ are carbon; or anisomer or pharmaceutically acceptable salt thereof.
 6. A compound ofclaim 5 wherein X is NR^(a); wherein R^(a) is selected from hydrido,methyl, ethyl, (4-trifluoromethyl)benzyl, (4-chloromethyl)benzyl,(4-methoxy)benzyl, (4-cyano)benzyl, and (4-nitro)benzyl; wherein R iscarboxyl; wherein R″ is selected from hydrido and ethenyl; wherein R¹ isselected from trifluoromethyl and pentafluoroethyl; wherein R² is one ormore radicals independently selected from hydrido, chloro, bromo,fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl,1-pentynyl, 3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy,methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl,pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy,benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,trifluoromethoxy, trifluoromethylthio, hydroxymethyl,hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl,N-methylamino, N-phenylamino, N-(benzyl)amino, nitro, cyano, amino,aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl,N-furylaminosulfonyl, N-(benzyl)aminosulfonyl,N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl,furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one ormore radicals selected from chloro, fluoro, bromo, methoxy, methylthioand methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted withchloro, furyl, furyl substituted with chloro, benzylcarbonyl,furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl, andmethylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon;or an isomer or pharmaceutically acceptable salt thereof.
 7. A compoundof claim 6 selected from compounds, and their isomers andpharmaceutically-acceptable salts, of the group consisting of6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;6,8-dichloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;6,7-difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;6-bromo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3-quinolinecarboxylicacid;6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid; 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid;6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-3-quinolinecarboxylicacid;6-chloro-1-[(4-chlorophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;6-chloro-1,2-dihydro-2-(trifluoromethyl)-1-[[4-(methoxy)phenyl]methyl]-3-quinolinecarboxylicacid;6-chloro-1-[(4-cyanophenyl)methyl]-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylicacid;6-chloro-1,2-dihydro-1-[(4-nitrophenyl)methyl]-2-(trifluoromethyl)-3-quinolinecarboxylicacid;6-chloro-1,2-dihydro-1-ethyl-2-(trifluoromethyl)-3-quinolinecarboxylicacid; and(S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid.8. A compound of Formula IIc:

wherein R^(a) is selected from hydrido and lower aralkyl; wherein R³ isselected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkoxy andhalo; wherein R⁴ is selected from hydrido, halo, lower alkyl, loweralkylthio, lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl,lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl,cyano, lower haloalkylthio, substituted or unsubstituted phenylcarbonyl,lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lowerdialkylaminosulfonyl, lower alkylaminosulfonyl, loweraralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6-memberedheteroaryl, lower hydrooxyalkyl, optionally substituted phenyl and 5- or6-membered nitrogen containing heterocyclosulfonyl; wherein R⁵ isselected from hydrido, lower alkyl, halo, lower haloalkyl, lower alkoxy,and phenyl; and wherein R⁶ is selected from hydrido, halo, cyano,hydrooxyiminomethyl, lower hydroxyalkyl, lower alkynyl, phenylalkynyl,lower alkyl, lower alkoxy, formyl and phenyl; or an isomer orpharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a therapeutically-effective amount of a compound,said compound selected from a family of compounds of claims 1–4, 5–7 and8; or a pharmaceutically-acceptable salt thereof.